Ruxolitinib formulation for reduction of itch in atopic dermatitis

ABSTRACT

This disclosure relates to methods of reducing itch in patients with atopic dermatitis and treating patients with atopic dermatitis by administering a topical 0.75% or 1.5% ruxolitinib cream two times per day.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/896,421, filed Sep. 5, 2019, U.S. Provisional Application No.62/897,059, filed Sep. 6, 2019, U.S. Provisional Application No.62/898,873, filed Sep. 11, 2019, U.S. Provisional Application No.62/983,252, filed Feb. 28, 2020, and U.S. Provisional Application No.63/020,668, filed May 6, 2020, each of which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

This disclosure relates to methods of reducing itch in patients withatopic dermatitis and treating patients with atopic dermatitis byadministering a topical ruxolitinib cream, including 0.75% or 1.5%ruxolitinib cream two times per day.

BACKGROUND

Atopic dermatitis affects approximately 10% of adults (Silverberg J I,Hanifin J M. J Allergy Clin Immunol 2013; 132:1132-1138), is increasingin incidence, and costs $3.8 billion a year in direct medical costsalone (Ellis C N, et al. J Am Acad Dermatol 2002; 46:361-370). Accordingto the recent Global Burden of Disease project, worldwide Atopicdermatitis (“AD”) is one of the 50 most prevalent diseases, and it hasthe second highest disability rank of all nonmalignant skin diseases(Hay R J, et al. J Invest Dermatol 2014; 134:1527-1534). Despite theadvances in targeted and numerous biologic treatments for psoriasis,only one such a therapy currently exist for AD (Dupixent®).

One of the main characteristics and a diagnostic criterion of AD ispruritus (itch). Itching brings about scratching, which in turn furtherdamages the AD skin, aggravates the disease and my lead to secondaryinfections. Further, nocturnal itching and scratching can result insleep loss and impairment in quality of life for patients and for theirimmediate family members, e.g., parents of a child with AD.

Topical therapies for AD are limited to topical steroids, topicalcalcineurin inhibitors and more recently a PDE4 inhibitor (Eucrisa®).These drugs have all limitations related to their efficacy levels,safety (particularly long-term use) or tolerability issues. Topicalsteroids use can also be associated with irreversible side effects, suchas skin atrophy or striae distensae. The use of systemic glucocorticoidsand calcineurin inhibitors is also limited because of their adverseevent (AE) profiles. If current topical therapies fail, then systemicimmunosuppressive agents (e.g., cyclosporine, methotrexate) areoccasionally employed with highly variable efficacy and/or high risk ofAEs.

Importantly, none of the presently available drugs exerts a directeffect on itch alleviation. Therefore, new approaches to promptly andeffectively control itch in patients with AD are needed. As mentioned,itch is the cardinal feature of AD and the symptom that leads directlyto a high disease (quality of life) burden in this condition. Thisdisclosure addresses this need and others.

SUMMARY

The present disclosure provides, inter alia, methods of reducing itch inand treating human patients having atopic dermatitis using ruxolitinib.Ruxolitinib is a potent JAK1/JAK2 inhibitor,(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile(INCB018424; ruxolitinib; active ingredient in JAKAFI®), and itspharmaceutically acceptable salts, has previously been described in U.S.Pat. No. 7,598,257, which is incorporated herein by reference in itsentirety. Ruxolitinib phosphate was previously described in U.S. PatentPubl. No. 2008/0312259, which is incorporated herein by reference in itsentirety.

For example, methods are provided for treating atopic dermatitis in ahuman patient, the method comprising administering to the skin of thehuman patient in need thereof, a cream formulation comprisingruxolitinib or a pharmaceutically acceptable salt thereof. In otherexamples, provided are methods of reducing itch in a human patient withatopic dermatitis, the method comprising administering to the skin ofthe human patient in need thereof, a cream formulation comprisingruxolitinib or a pharmaceutically acceptable salt thereof, wherein thepatient achieves a reduction in the itch Numerical Rating Scale scorefrom baseline.

The present disclosure also provides methods of reducing itch in a humanpatient with atopic dermatitis, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib, or a pharmaceutically acceptable salt thereof,

-   -   wherein said patient achieves a reduction in the itch Numerical        Rating Scale score from baseline.

The present disclosure also provides methods of reducing itch in a humanpatient with atopic dermatitis, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib, or a pharmaceutically acceptable salt thereof,

-   -   wherein said patient achieves a reduction in the itch Numerical        Rating Scale score from baseline.

The present disclosure further provides methods of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day (BID), wherein said cream formulation comprises 1.5% (w/w)on a free base basis of ruxolitinib phosphate,

-   -   wherein said patient achieves a reduction in the itch Numerical        Rating Scale score from baseline.

The present disclosure also provides methods of reducing itch in a humanpatient with atopic dermatitis, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday (BID), wherein said cream formulation comprises 0.75% (w/w) on afree base basis of ruxolitinib phosphate,

-   -   wherein said patient achieves a reduction in the itch Numerical        Rating Scale score from baseline.

The present disclosure also provides methods of reducing itch in a humanpatient with atopic dermatitis, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday (BID), wherein said cream formulation comprises 0.75% (w/w) on afree base basis of ruxolitinib phosphate,

-   -   wherein said patient achieves a reduction in the itch Numerical        Rating Scale score from baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib, or a pharmaceutically acceptable salt thereof.

The present disclosure further provides methods of treating atopicdermatitis in a human patient, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib phosphate. The present disclosure also providesmethods of reducing itch in a human patient with atopic dermatitis,comprising administering to the skin of said human patient in needthereof, a cream formulation two times per day, wherein said creamformulation is an oil-in-water emulsion, comprising 1.5% (w/w) on a freebase basis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks        (e.g., such as for 12 weeks),    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of the        administering.

The present disclosure also provides methods of reducing itch in a humanpatient with atopic dermatitis, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation is an oil-in-water emulsion,comprising 0.75% (w/w) on a free base basis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks        (e.g., such as for 12 weeks),    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of the        administering.

The present disclosure further provides methods of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 1.5% (w/w) on a free base basis of ruxolitinibphosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering, and    -   wherein the patient:        -   is aged 18 to 70 years,        -   has been diagnosed with atopic dermatitis for at least 2            years,        -   has an Investigator's Global Assessment score of 2 to 3 at            screening and baseline, and        -   has a Body Surface Area of atopic dermatitis involvement            (excluding face and intertriginous areas) of 3% to 20% at            baseline.

The present disclosure further provides methods of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 0.75% (w/w) or 1.5% (w/w) on a free base basis ofruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering, and    -   wherein the patient:    -   is an adolescent aged ≥12 to 17, inclusive, or a man or woman        aged ≥18 years;    -   has history of AD for at least 2 years;    -   has an Investigator's Global Assessment score of 2 to 3 at        baseline; and    -   has a % BSA of AD involvement, excluding the scalp, of 3% to 20%        at baseline.

The present disclosure also provides methods of reducing itch in a humanpatient with atopic dermatitis, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation is an oil-in-water emulsion,comprising 1.5% (w/w) on a free base basis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering, and    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering.

The present disclosure also provides methods of reducing itch in a humanpatient with atopic dermatitis, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation is an oil-in-water emulsion,comprising 0.75% (w/w) on a free base basis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering, and    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering.

The present disclosure further provides methods of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 1.5% (w/w) on a free base basis of ruxolitinibphosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein the patient:    -   is aged 18 to 70 years,    -   has been diagnosed with atopic dermatitis for at least 2 years,    -   has an Investigator's Global Assessment score of 2 to 3 at        screening and baseline, and    -   has a Body Surface Area of atopic dermatitis involvement        (excluding face and intertriginous areas) of 3% to 20% at        baseline.

The present disclosure further provides methods of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 0.75% (w/w) or 1.5% (w/w) on a free base basis ofruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein the patient:    -   is an adolescent aged ≥12 to 17, inclusive, or a man or woman        aged ≥18 years;    -   has history of AD for at least 2 years;    -   has an Investigator's Global Assessment score of 2 to 3 at        baseline; and    -   has a % BSA of AD involvement, excluding the scalp, of 3% to 20%        at baseline.

The present disclosure also provides methods of treating moderate atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a topical formulation two times perday, wherein said topical formulation comprises 0.75% (w/w) or 1.5%(w/w) on a free base basis of ruxolitinib, or a pharmaceuticallyacceptable salt thereof.

The present disclosure also provides methods of treating moderate tosevere atopic dermatitis in a human patient comprising administering tothe skin of said human patient in need thereof, a topical formulationtwo times per day, wherein said topical formulation comprises 0.75%(w/w) or 1.5% (w/w) on a free base basis of ruxolitinib, or apharmaceutically acceptable salt thereof.

The present disclosure also provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a topical formulation two times perday, wherein the topical formulation comprises 0.75% (w/w) or 1.5% (w/w)on a free base basis of ruxolitinib, or a pharmaceutically acceptablesalt thereof,

-   -   wherein said patient has: an Eczema Area and Severity Index        score of ≥16 at baseline; and    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline.

The present disclosure further provides a topical formulation (e.g., acream formulation) comprising 0.75% (w/w) on a free base basis ofruxolitinib, or a pharmaceutically acceptable salt thereof, for use inany of the methods described herein.

The present disclosure also provides a topical formulation (e.g., acream formulation) comprising 1.5% (w/w) on a free base basis ofruxolitinib, or a pharmaceutically acceptable salt thereof, for use inany of the methods described herein.

The present disclosure further provides use of a topical formulation(e.g., a cream formulation) comprising 0.75% (w/w) on a free base basisof ruxolitinib, or a pharmaceutically acceptable salt thereof, formanufacture of a medicament for use in any of the methods describedherein.

The present disclosure further provides use of a topical formulation(e.g., a cream formulation) comprising 1.5% (w/w) on a free base basisof ruxolitinib, or a pharmaceutically acceptable salt thereof, formanufacture of a medicament for use in any of the methods describedherein.

DESCRIPTION OF DRAWINGS

“RUX” in the Figures is ruxolitinib phosphate. TAC in the Figures istriamcinolone.

FIG. 1 shows a graph of mean percentage improvement from baseline inEASI scores for vehicle (BID), triamcinolone (0.1% BID), and ruxolitinibcream (0.15% QD, 0.5% QD, 1.5% QD, and 1.5% BID) at week 2 (first graphbar of each set), week 4 (second graph bar of each set) and week 8(third graph bar of each set). 0.1% TAC does not show a bar because TACwas only administered for 4 weeks.

FIG. 2 shows a graph of mean percentage improvement from baseline inEASI scores for vehicle (BID), triamcinolone (0.1% BID), and ruxolitinibcream (1.5% BID) at week 2 (first graph bar of each set), week 4 (secondgraph bar of each set) and week 8 (third graph bar of each set). 0.1%TAC does not show a bar because TAC was only administered for 4 weeks.

FIG. 3 shows a graph of percentage of EASI-75 responders (at least a 75%improvement in EASI from baseline) for vehicle (BID), triamcinolone(0.1% BID), and ruxolitinib cream (0.15% QD, 0.5% QD, 1.5% QD, and 1.5%BID) at week 2 (first graph bar of each set), week 4 (second graph barof each set) and week 8 (third graph bar of each set). 0.1% TAC does notshow a bar because TAC was only administered for 4 weeks.

FIG. 4 shows a graph of proportion of IGA response (a responder was apatient achieving an IGA score of 0-1 with an improvement of ≥2 pointsfrom baseline) for vehicle (BID), triamcinolone (0.1% BID), andruxolitinib cream (0.15% QD, 0.5% QD, 1.5% QD, and 1.5% BID) at week 2(first graph bar of each set), week 4 (second graph bar of each set) andweek 8 (third graph bar of each set). 0.1% TAC does not show a barbecause TAC was only administered for 4 weeks.

FIG. 5 shows a graph of mean percentage improvement from baseline inEASI scores for vehicle, triamcinolone, and ruxolitinib cream in 12weeks. The open-label period was from week 8 to week 12, wherein 1.5%ruxolitinib cream was administered.

FIG. 6 shows a graph of proportion of IGA response for vehicle,triamcinolone, and ruxolitinib cream in 12 weeks. The open-label periodwas from week 8 to week 12, wherein 1.5% ruxolitinib cream wasadministered.

FIG. 7 shows a graph of mean change from baseline in daily itch NRSscores (NRS score has a range of 0-10 with 0 being no itch and 10 beingthe worst possible itch) for vehicle (BID), triamcinolone (0.1% BID),and ruxolitinib cream (0.15% QD, 0.5% QD, 1.5% QD, and 1.5% BID) in 28days.

FIG. 8 shows a graph of mean change from baseline in daily itch NRSscores for vehicle (BID), triamcinolone (0.1% BID), and ruxolitinibcream (1.5% BID) in 28 days.

FIG. 9 shows a graph of mean itch NRS scores for vehicle, triamcinolone,and ruxolitinib cream in 12 weeks. The open-label period was from week 8to week 12, wherein 1.5% ruxolitinib cream was administered.

FIG. 10 shows a graph of mean percentage improvement from baseline inSkindex-16 overall score for vehicle (BID), triamcinolone (0.1% BID),and ruxolitinib cream (0.15% QD, 0.5% QD, 1.5% QD, and 1.5% BID) at week2 (first graph bar of each set), week 4 (second graph bar of each set)and week 8 (third graph bar of each set). 0.1% TAC does not show a barbecause TAC was only administered for 4 weeks. ** indicates P<0.01 vsvehicle; *** indicates P<0.001 vs vehicle. † indicates TAC arm received0.1% TAC cream through Week 4 and vehicle thereafter.

FIG. 11 depicts the proportion of participants that achieved IGA-TS inthe vehicle control period at Week 2, Week 4, and Week 8 for TRuE-AD1(Study 303) (solid bars) and TRuE-AD2 (Study 304) (striped bars) forvehicle, 0.75% BID ruxolitinib cream, and 1.5% BID ruxolitinib cream(first bar of each set is vehicle; second bar of each set is 0.75% BIDruxolitinib cream; and third bar of each set is 1.5% ruxolitinib cream).

FIG. 12 depicts the proportion of participants that achieved EASI75 inthe vehicle control period at Week 2, Week 4, and Week 8 for TRuE-AD1(Study 303) (solid bars) and TRuE-AD2 (Study 304) (striped bars) forvehicle, 0.75% BID ruxolitinib cream, and 1.5% BID ruxolitinib cream(first bar of each set is vehicle; second bar of each set is 0.75% BIDruxolitinib cream; and third bar of each set is 1.5% ruxolitinib cream).

FIG. 13 depicts the proportion of participants that achieved a ≥4-pointimprovement in itch NRS score in the vehicle control period at Week 2,Week 4, and Week 8 for TRuE-AD1 (Study 303) (solid bars) and TRuE-AD2(Study 304) (striped bars) for vehicle, 0.75% BID ruxolitinib cream, and1.5% BID ruxolitinib cream for patients having baseline itch NRS≥4(first bar of each set is vehicle; second bar of each set is 0.75% BIDruxolitinib cream; and third bar of each set is 1.5% ruxolitinib cream).

FIG. 14 depicts the mean change from baseline in daily itch NRS scorefrom Day 1 to Day 28 for TRuE-AD1 (Study 303) for vehicle (top line),0.75% BID ruxolitinib cream (middle line), and 1.5% BID ruxolitinibcream (bottom line) for patients having baseline itch NRS≥4.

FIG. 15 depicts the mean change from baseline in daily itch NRS scorefrom Day 1 to Day 28 for TRuE-AD2 (Study 304) for vehicle (top line),0.75% BID ruxolitinib cream (middle line), and 1.5% BID ruxolitinibcream (bottom line) for patients having baseline itch NRS≥4.

FIG. 16 depicts the proportion of participants that achieved a ≥6-pointimprovement in the PROMIS sleep disturbance score (8b) in the vehiclecontrol period at Week 2, Week 4, and Week 8 for TRuE-AD1 (Study 303)(solid bars) and TRuE-AD2 (Study 304) (striped bars) for vehicle, 0.75%BID ruxolitinib cream, and 1.5% BID ruxolitinib cream (first bar of eachset is vehicle; second bar of each set is 0.75% BID ruxolitinib cream;and third bar of each set is 1.5% ruxolitinib cream).

FIG. 17 depicts the proportion of participants that achieved a ≥6-pointimprovement in the PROMIS sleep impairment score (8a) in the vehiclecontrol period at Week 2, Week 4, and Week 8 for TRuE-AD1 (Study 303)(solid bars) and TRuE-AD2 (Study 304) (striped bars) for vehicle, 0.75%BID ruxolitinib cream, and 1.5% BID ruxolitinib cream (first bar of eachset is vehicle; second bar of each set is 0.75% BID ruxolitinib cream;and third bar of each set is 1.5% ruxolitinib cream).

FIG. 18 shows a box plot of change from baseline in hemoglobin (g/L) inthe vehicle control period at Week 2, Week 4, and Week 8 for TRuE-AD1(Study 303) for vehicle, 0.75% BID ruxolitinib cream, and 1.5% BIDruxolitinib cream (first bar of each set is vehicle; second bar of eachset is 0.75% BID ruxolitinib cream; and third bar of each set is 1.5%ruxolitinib cream).

FIG. 19 shows a box plot of change from baseline in platelets (10⁹/L) inthe vehicle control period at Week 2, Week 4, and Week 8 for TRuE-AD1(Study 303) for vehicle, 0.75% BID ruxolitinib cream, and 1.5% BIDruxolitinib cream (first bar of each set is vehicle; second bar of eachset is 0.75% BID ruxolitinib cream; and third bar of each set is 1.5%ruxolitinib cream).

FIG. 20 shows a box plot of change from baseline in hemoglobin (g/L) inthe vehicle control period at Week 2, Week 4, and Week 8 for TRuE-AD2(Study 304) for vehicle, 0.75% BID ruxolitinib cream, and 1.5% BIDruxolitinib cream (first bar of each set is vehicle; second bar of eachset is 0.75% BID ruxolitinib cream; and third bar of each set is 1.5%ruxolitinib cream).

FIG. 21 shows a box plot of change from baseline in platelets (10⁹/L) inthe vehicle control period at Week 2, Week 4, and Week 8 for TRuE-AD2(Study 304) for vehicle, 0.75% BID ruxolitinib cream, and 1.5% BIDruxolitinib cream (first bar of each set is vehicle; second bar of eachset is 0.75% BID ruxolitinib cream; and third bar of each set is 1.5%ruxolitinib cream).

FIG. 22 depicts the proportion of participants that achieved IGA-TS inthe vehicle control period at Week 2, Week 4, and Week 8 for patientswho have a Body Surface Area of atopic dermatitis involvement of ≥10% atbaseline and an Eczema Area and Severity Index score of ≥16 at baselinein both TRuE-AD1 (Study 303) and TRuE-AD2 (Study 304) for vehicle, 0.75%BID ruxolitinib cream, and 1.5% BID ruxolitinib cream (first bar of eachset is vehicle; second bar of each set is 0.75% BID ruxolitinib cream;and third bar of each set is 1.5% ruxolitinib cream).

FIG. 23 depicts the proportion of participants that achieved EASI-75 inthe vehicle control period at Week 2, Week 4, and Week 8 for thepatients who a Body Surface Area of atopic dermatitis involvement of≥10% at baseline and an Eczema Area and Severity Index score of ≥16 atbaseline in both TRuE-AD1 (Study 303) and TRuE-AD2 (Study 304) forvehicle, 0.75% BID ruxolitinib cream, and 1.5% BID ruxolitinib cream(first bar of each set is vehicle; second bar of each set is 0.75% BIDruxolitinib cream; and third bar of each set is 1.5% ruxolitinib cream).

FIG. 24 depicts the proportion of participants that achieved a ≥4-pointimprovement in itch NRS score in the vehicle control period at Week 2,Week 4, and Week 8 for the patients who a Body Surface Area of atopicdermatitis involvement of ≥10% at baseline, an Eczema Area and SeverityIndex score of ≥16 at baseline, and an itch Numerical Rating Scale scoreof ≥4 at baseline in both TRuE-AD1 (Study 303) and TRuE-AD2 (Study 304)for vehicle, 0.75% BID ruxolitinib cream, and 1.5% BID ruxolitinib creamfor patients having baseline itch NRS≥4 (first bar of each set isvehicle; second bar of each set is 0.75% BID ruxolitinib cream; andthird bar of each set is 1.5% ruxolitinib cream).

FIG. 25 depicts mean change from baseline in daily itch NRS scores fromday 1 to day 28 (patients having a baseline itch NRS score of ≥4) forthe pooled TRuE-AD1 (Study 303) and TRuE-AD2 (Study 304) studies (topline (vehicle), middle line (0.75% BID ruxolitinib cream), and bottomline (1.5% BID ruxolitinib cream).

FIG. 26 depicts proportion of patients achieving an itch NRS score of≥4-point improvement in itch NRS score for day 1 to day 7 (patientshaving a baseline itch NRS score of ≥4) for the pooled TRuE-AD1 (Study303) and TRuE-AD2 (Study 304) studies (first bar (vehicle), second bar(0.75% BID ruxolitinib cream), and third bar (1.5% BID ruxolitinibcream).

FIG. 27 depicts the proportion of participants that achieved IGA-TS inthe vehicle control period at Week 2, Week 4, and Week 8 for the pooledTRuE-AD1 (Study 303) and TRuE-AD2 (Study 304) studies for vehicle, 0.75%BID ruxolitinib cream, and 1.5% BID ruxolitinib cream (first bar of eachset is vehicle; second bar of each set is 0.75% BID ruxolitinib cream;and third bar of each set is 1.5% ruxolitinib cream).

FIG. 28 depicts the proportion of participants that achieved EASI-75 inthe vehicle control period at Week 2, Week 4, and Week 8 for the pooledTRuE-AD1 (Study 303) and TRuE-AD2 (Study 304) for vehicle, 0.75% BIDruxolitinib cream, and 1.5% BID ruxolitinib cream (first bar of each setis vehicle; second bar of each set is 0.75% BID ruxolitinib cream; andthird bar of each set is 1.5% ruxolitinib cream).

FIG. 29 depicts the proportion of participants that achieved ≥6-PointImprovement in the PROMIS Sleep Disturbance Score (8b) in the vehiclecontrol period at Week 2, Week 4, and Week 8 for patients who have aPROMIS Sleep Disturbance Score (8b)≥6 at baseline for the pooledTRuE-AD1 (Study 303) and TRuE-AD2 (Study 304) for vehicle, 0.75% BIDruxolitinib cream, and 1.5% BID ruxolitinib cream (first bar of each setis vehicle; second bar of each set is 0.75% BID ruxolitinib cream; andthird bar of each set is 1.5% ruxolitinib cream).

FIG. 30 depicts the proportion of participants that achieved ≥6-PointImprovement in the PROMIS Sleep-Related Impairment (8a) in the vehiclecontrol period at Week 2, Week 4, and Week 8 for patients who have aPROMIS Sleep-Related Impairment (8a)≥6 at baseline for the pooledTRuE-AD1 (Study 303) and TRuE-AD2 (Study 304) for vehicle, 0.75% BIDruxolitinib cream, and 1.5% BID ruxolitinib cream (first bar of each setis vehicle; second bar of each set is 0.75% BID ruxolitinib cream; andthird bar of each set is 1.5% ruxolitinib cream).

FIG. 31 shows a graph of mean in EASI scores in the vehicle controlperiod at Baseline, Week 2, Week 4, and Week 8 for the pooled TRuE-AD1(Study 303) and TRuE-AD2 (Study 304) (top line (vehicle), middle line(0.75% BID ruxolitinib cream), and bottom line (1.5% BID ruxolitinibcream).

FIG. 32 shows a graph of mean score change from baseline in EASI scoresin the vehicle control period at Baseline, Week 2, Week 4, and Week 8for the pooled TRuE-AD1 (Study 303) and TRuE-AD2 (Study 304) (top line(vehicle), middle line (1.5% BID ruxolitinib cream), and bottom line(0.75% BID ruxolitinib cream).

FIG. 33 shows a graph of mean percentage change from baseline in EASIscores in the vehicle control period at Baseline, Week 2, Week 4, andWeek 8 for the pooled TRuE-AD1 (Study 303) and TRuE-AD2 (Study 304) (topline (vehicle), middle line (1.5% BID ruxolitinib cream), and bottomline (0.75% BID ruxolitinib cream).

DETAILED DESCRIPTION

The present disclosure provides, inter alia, a method of reducing itchin a human patient with atopic dermatitis, comprising administering tothe skin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 1.5% (w/w) on afree base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof,

-   -   wherein said patient achieves a reduction in the itch Numerical        Rating Scale score from baseline.

The present disclosure also provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 0.75% (w/w) on afree base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof,

-   -   wherein said patient achieves a reduction in the itch Numerical        Rating Scale score from baseline.

The present disclosure further provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 1.5% (w/w) on afree base basis of ruxolitinib phosphate,

-   -   wherein said patient achieves a reduction in the itch Numerical        Rating Scale score from baseline.

The present disclosure further provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 0.75% (w/w) on afree base basis of ruxolitinib phosphate,

-   -   wherein said patient achieves a reduction in the itch Numerical        Rating Scale score from baseline.

In some embodiments, the method provides prompt reduction in itch in thepatient.

The present disclosure further provides a method of treating atopicdermatitis in a human patient, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) or 1.5% (w/w)on a free base basis of ruxolitinib, or a pharmaceutically acceptablesalt thereof.

The present disclosure further provides methods of treating atopicdermatitis in a human patient, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib, or a pharmaceutically acceptable salt thereof.

The present disclosure further provides methods of treating atopicdermatitis in a human patient, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib phosphate.

The present disclosure further provides a method of treating atopicdermatitis in a human patient, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib, or a pharmaceutically acceptable salt thereof.

The present disclosure further provides a method of treating atopicdermatitis in a human patient, comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib phosphate.

In some embodiments, the ruxolitinib, or a pharmaceutically acceptablesalt thereof, is ruxolitinib phosphate.

In some embodiments, the patient achieves Investigator's GlobalAssessment score of 0 or 1 with an improvement of at least 2 points frombaseline.

In some embodiments, the patient achieves a 75% improvement in EczemaArea and Severity Index score from baseline.

The present disclosure further provides a method of treating mild tomoderate atopic dermatitis in a human patient comprising administeringto the skin of said human patient in need thereof, a topical formulationtwo times per day, wherein said topical formulation comprises 0.75%(w/w) or 1.5% (w/w) on a free base basis of ruxolitinib, or apharmaceutically acceptable salt thereof.

The present disclosure further provides a method of treating mild tomoderate atopic dermatitis in a human patient comprising administeringto the skin of said human patient in need thereof, a topical formulationtwo times per day, wherein said topical formulation comprises 0.75%(w/w) on a free base basis of ruxolitinib, or a pharmaceuticallyacceptable salt thereof.

The present disclosure also provides a method of treating mild tomoderate atopic dermatitis in a human patient comprising administeringto the skin of said human patient in need thereof, a topical formulationtwo times per day, wherein said topical formulation comprises 1.5% (w/w)on a free base basis of ruxolitinib, or a pharmaceutically acceptablesalt thereof.

The present disclosure further provides a method of treating mild tomoderate atopic dermatitis in a human patient comprising administeringto the skin of said human patient in need thereof, a topical formulationtwo times per day, wherein said topical formulation comprises 0.75%(w/w) on a free base basis of ruxolitinib phosphate.

The present disclosure also provides a method of treating mild tomoderate atopic dermatitis in a human patient comprising administeringto the skin of said human patient in need thereof, a topical formulationtwo times per day, wherein said topical formulation comprises 1.5% (w/w)on a free base basis of ruxolitinib phosphate.

The present disclosure further provides a method of treating mild tomoderate atopic dermatitis in a human patient comprising administeringto the skin of said human patient in need thereof, a cream formulationtwo times per day, wherein said cream formulation comprises 0.75% (w/w)or 1.5% (w/w) on a free base basis of ruxolitinib, or a pharmaceuticallyacceptable salt thereof.

The present disclosure further provides a method of treating mild tomoderate atopic dermatitis in a human patient comprising administeringto the skin of said human patient in need thereof, a cream formulationtwo times per day, wherein said cream formulation comprises 0.75% (w/w)on a free base basis of ruxolitinib, or a pharmaceutically acceptablesalt thereof.

The present disclosure also provides a method of treating mild tomoderate atopic dermatitis in a human patient comprising administeringto the skin of said human patient in need thereof, a cream formulationtwo times per day, wherein said cream formulation comprises 1.5% (w/w)on a free base basis of ruxolitinib, or a pharmaceutically acceptablesalt thereof.

The present disclosure further provides a method of treating mild tomoderate atopic dermatitis in a human patient comprising administeringto the skin of said human patient in need thereof, a cream formulationtwo times per day, wherein said cream formulation comprises 0.75% (w/w)on a free base basis of ruxolitinib phosphate.

The present disclosure also provides a method of treating mild tomoderate atopic dermatitis in a human patient comprising administeringto the skin of said human patient in need thereof, a cream formulationtwo times per day, wherein said cream formulation comprises 1.5% (w/w)on a free base basis of ruxolitinib phosphate.

The present disclosure further provides a method of treating moderateatopic dermatitis in a human patient comprising administering to theskin of said human patient in need thereof, a topical formulation twotimes per day, wherein said topical formulation comprises 0.75% (w/w) or1.5% (w/w) on a free base basis of ruxolitinib, or a pharmaceuticallyacceptable salt thereof.

The present disclosure further provides a method of treating moderateatopic dermatitis in a human patient comprising administering to theskin of said human patient in need thereof, a topical formulation twotimes per day, wherein said topical formulation comprises 0.75% (w/w) ona free base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof.

The present disclosure also provides a method of treating moderateatopic dermatitis in a human patient comprising administering to theskin of said human patient in need thereof, a topical formulation twotimes per day, wherein said topical formulation comprises 1.5% (w/w) ona free base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof.

The present disclosure further provides a method of treating moderateatopic dermatitis in a human patient comprising administering to theskin of said human patient in need thereof, a topical formulation twotimes per day, wherein said topical formulation comprises 0.75% (w/w) ona free base basis of ruxolitinib phosphate.

The present disclosure also provides a method of treating moderateatopic dermatitis in a human patient comprising administering to theskin of said human patient in need thereof, a topical formulation twotimes per day, wherein said topical formulation comprises 1.5% (w/w) ona free base basis of ruxolitinib phosphate.

The present disclosure further provides a method of treating moderateatopic dermatitis in a human patient comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 0.75% (w/w) or1.5% (w/w) on a free base basis of ruxolitinib, or a pharmaceuticallyacceptable salt thereof.

The present disclosure further provides a method of treating moderateatopic dermatitis in a human patient comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 0.75% (w/w) on afree base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof.

The present disclosure also provides a method of treating moderateatopic dermatitis in a human patient comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 1.5% (w/w) on afree base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof.

The present disclosure further provides a method of treating moderateatopic dermatitis in a human patient comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 0.75% (w/w) on afree base basis of ruxolitinib phosphate.

The present disclosure also provides a method of treating moderateatopic dermatitis in a human patient comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 1.5% (w/w) on afree base basis of ruxolitinib phosphate.

The present disclosure also provides a method of treating moderate tosevere atopic dermatitis in a human patient comprising administering tothe skin of said human patient in need thereof, a topical formulationtwo times per day, wherein said topical formulation comprises 0.75%(w/w) or 1.5% (w/w) on a free base basis of ruxolitinib, or apharmaceutically acceptable salt thereof.

The present disclosure further provides a method of treating moderate tosevere atopic dermatitis in a human patient comprising administering tothe skin of said human patient in need thereof, a topical formulationtwo times per day, wherein said topical formulation comprises 0.75%(w/w) on a free base basis of ruxolitinib, or a pharmaceuticallyacceptable salt thereof.

The present disclosure also provides a method of treating moderate tosevere atopic dermatitis in a human patient comprising administering tothe skin of said human patient in need thereof, a topical formulationtwo times per day, wherein said topical formulation comprises 1.5% (w/w)on a free base basis of ruxolitinib, or a pharmaceutically acceptablesalt thereof.

The present disclosure further provides a method of treating moderate tosevere atopic dermatitis in a human patient comprising administering tothe skin of said human patient in need thereof, a topical formulationtwo times per day, wherein said topical formulation comprises 0.75%(w/w) on a free base basis of ruxolitinib phosphate.

The present disclosure also provides a method of treating moderate tosevere atopic dermatitis in a human patient comprising administering tothe skin of said human patient in need thereof, a topical formulationtwo times per day, wherein said topical formulation comprises 1.5% (w/w)on a free base basis of ruxolitinib phosphate.

The present disclosure also provides a method of treating moderate tosevere atopic dermatitis in a human patient comprising administering tothe skin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 0.75% (w/w) or1.5% (w/w) on a free base basis of ruxolitinib, or a pharmaceuticallyacceptable salt thereof.

The present disclosure further provides a method of treating moderate tosevere atopic dermatitis in a human patient comprising administering tothe skin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 0.75% (w/w) on afree base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof.

The present disclosure also provides a method of treating moderate tosevere atopic dermatitis in a human patient comprising administering tothe skin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 1.5% (w/w) on afree base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof.

The present disclosure further provides a method of treating moderate tosevere atopic dermatitis in a human patient comprising administering tothe skin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 0.75% (w/w) on afree base basis of ruxolitinib phosphate.

The present disclosure also provides a method of treating moderate tosevere atopic dermatitis in a human patient comprising administering tothe skin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 1.5% (w/w) on afree base basis of ruxolitinib phosphate.

In some embodiments of the embodiments in the preceding twentyparagraphs, the patient achieves at least a 4-point reduction in itchNumerical Rating Scale score from baseline. In some embodiments of theembodiments in the preceding twenty paragraphs, the patient achieves anInvestigator's Global Assessment score of 0 or 1 with an improvement ofat least 2 points from baseline. In some embodiments of the embodimentsin the preceding twenty paragraphs, the patient achieves a statisticallysignificant improvement in Eczema Area and Severity Index score frombaseline. In some embodiments of the embodiments in the preceding twentyparagraphs, the patient achieves a 75% improvement in Eczema Area andSeverity Index score from baseline. In some embodiments of theembodiments in the preceding twenty paragraphs, the patient achieves atleast a 4-point reduction in itch Numerical Rating Scale score frombaseline; and the patient achieves an Investigator's Global Assessmentscore of 0 or 1 with an improvement of at least 2 points from baseline.In some embodiments of the embodiments in the preceding twentyparagraphs, the patient achieves at least a 4-point reduction in itchNumerical Rating Scale score from baseline; and the patient achieves a75% improvement in Eczema Area and Severity Index score from baseline.In some embodiments of the embodiments in the preceding twentyparagraphs, the patient achieves an Investigator's Global Assessmentscore of 0 or 1 with an improvement of at least 2 points from baseline;and the patient achieves a 75% improvement in Eczema Area and SeverityIndex score from baseline. In some embodiments of the embodiments in thepreceding twenty paragraphs, the patient achieves at least a 4-pointreduction in itch Numerical Rating Scale score from baseline; thepatient achieves an Investigator's Global Assessment score of 0 or 1with an improvement of at least 2 points from baseline; and the patientachieves a 75% improvement in Eczema Area and Severity Index score frombaseline. In some embodiments of the embodiments in the preceding twentyparagraphs, the patient achieves at least a 4-point reduction in itchNumerical Rating Scale score from baseline at week 4 of saidadministering. In some embodiments of the embodiments in the precedingtwenty paragraphs, the patient achieves at least a 4-point reduction initch Numerical Rating Scale score from baseline at week 8 of saidadministering. In some embodiments of the embodiments in the precedingtwenty paragraphs, the patient achieves an Investigator's GlobalAssessment score of 0 or 1 with an improvement of at least 2 points frombaseline at week 4 of said administering. In some embodiments of theembodiments in the preceding twenty paragraphs, the patient achieves anInvestigator's Global Assessment score of 0 or 1 with an improvement ofat least 2 points from baseline at week 8 of said administering. In someembodiments of the embodiments in the preceding twenty paragraphs, thepatient achieves a 75% improvement in Eczema Area and Severity Indexscore from baseline at week 4 of said administering. In some embodimentsof the embodiments in the preceding twenty paragraphs, the patientachieves a 75% improvement in Eczema Area and Severity Index score frombaseline at week 8 of said administering. In some embodiments of theembodiments in the preceding twenty paragraphs, the patient achieves atleast a 4-point reduction in itch Numerical Rating Scale score frombaseline at week 4 of said administering; and the patient achieves anInvestigator's Global Assessment score of 0 or 1 with an improvement ofat least 2 points from baseline at week 4 of said administering. In someembodiments of the embodiments in the preceding twenty paragraphs, thepatient achieves at least a 4-point reduction in itch Numerical RatingScale score from baseline at week 8 of said administering; and thepatient achieves an Investigator's Global Assessment score of 0 or 1with an improvement of at least 2 points from baseline at week 8 of saidadministering. In some embodiments of the embodiments in the precedingtwenty paragraphs, the patient achieves at least a 4-point reduction initch Numerical Rating Scale score from baseline at week 4 of saidadministering; and the patient achieves a 75% improvement in Eczema Areaand Severity Index score from baseline at week 4 of said administering.In some embodiments of the embodiments in the preceding twentyparagraphs, the patient achieves at least a 4-point reduction in itchNumerical Rating Scale score from baseline at week 8 of saidadministering; and the patient achieves a 75% improvement in Eczema Areaand Severity Index score from baseline at week 8 of said administering.In some embodiments of the embodiments in the preceding twentyparagraphs, the patient achieves an Investigator's Global Assessmentscore of 0 or 1 with an improvement of at least 2 points from baselineat week 4 of said administering; and the patient achieves a 75%improvement in Eczema Area and Severity Index score from baseline atweek 4 of said administering. In some embodiments of the embodiments inthe preceding twenty paragraphs, the patient achieves an Investigator'sGlobal Assessment score of 0 or 1 with an improvement of at least 2points from baseline at week 8 of said administering; and the patientachieves a 75% improvement in Eczema Area and Severity Index score frombaseline at week 8 of said administering. In some embodiments of theembodiments in the preceding twenty paragraphs, the patient achieves atleast a 4-point reduction in itch Numerical Rating Scale score frombaseline at week 4 of said administering; the patient achieves anInvestigator's Global Assessment score of 0 or 1 with an improvement ofat least 2 points from baseline at week 4 of said administering; and thepatient achieves a 75% improvement in Eczema Area and Severity Indexscore from baseline at week 4 of said administering. In some embodimentsof the embodiments in the preceding twenty paragraphs, the patientachieves at least a 4-point reduction in itch Numerical Rating Scalescore from baseline at week 8 of said administering; the patientachieves an Investigator's Global Assessment score of 0 or 1 with animprovement of at least 2 points from baseline at week 8 of saidadministering; and the patient achieves a 75% improvement in Eczema Areaand Severity Index score from baseline at week 8 of said administering.In some embodiments of the embodiments in the preceding twentyparagraphs, the administering is maintained for at least 4 weeks. Insome embodiments of the embodiments in the preceding twenty paragraphs,the administering is maintained for at least 8 weeks.

Generally, mild to moderate, moderate, and moderate to severe atopicdermatitis is defined by FDA—i.e., in terms of Investigator's GlobalAssessment score at baseline (see definition of IGA supra). For example,patients with mild atopic dermatitis have an Investigator's GlobalAssessment score of 2 at baseline; patients with moderate atopicdermatitis have an Investigator's Global Assessment score of 3 atbaseline; and patients with severe atopic dermatitis have anInvestigator's Global Assessment score of 4 at baseline. Patients withmild to moderate atopic dermatitis have an Investigator's GlobalAssessment score of 2 to 3 at baseline, while patients with moderate tosevere atopic dermatitis have an Investigator's Global Assessment scoreof 3 to 4 at baseline.

In some embodiments, the patient with mild to moderate atopic dermatitishas a Body Surface Area of atopic dermatitis involvement of ≥10% atbaseline. In some embodiments, the patient with moderate atopicdermatitis has a Body Surface Area of atopic dermatitis involvement of≥10% at baseline. In some embodiments, the patient with moderate tosevere atopic dermatitis has a Body Surface Area of atopic dermatitisinvolvement of ≥10% at baseline.

In some embodiments, the patient with mild to moderate atopic dermatitishas a Body Surface Area of atopic dermatitis involvement of from 10% to20% at baseline. In some embodiments, the patient with moderate atopicdermatitis has a Body Surface Area of atopic dermatitis involvement offrom 10% to 20% at baseline. In some embodiments, the patient withmoderate to severe atopic dermatitis has a Body Surface Area of atopicdermatitis involvement of from 10% to 20% at baseline.

In some embodiments, the patient with moderate atopic dermatitis has anEczema Area and Severity Index of ≥16 at baseline. In some embodiments,the patient with moderate to severe atopic dermatitis has an Eczema Areaand Severity Index of ≥16 at baseline.

In some embodiments, the patient with moderate atopic dermatitis hasInvestigator's Global Assessment score of 3 and a Body Surface Area ofatopic dermatitis involvement of from 10% to 20% at baseline.

In some embodiments, the patient with moderate to severe atopicdermatitis has an Eczema Area and Severity Index of ≥16 at baseline, aBody Surface Area of atopic dermatitis involvement of ≥10% at baseline,and an Investigator's Global Assessment score of 3 to 4.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a topical formulation two times perday, wherein the topical formulation comprises 0.75% (w/w) or 1.5% (w/w)on a free base basis of ruxolitinib, or a pharmaceutically acceptablesalt thereof,

-   -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline; and    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a topical formulation two times perday, wherein the topical formulation comprises 0.75% (w/w) on a freebase basis of ruxolitinib, or a pharmaceutically acceptable saltthereof,

-   -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline; and    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a topical formulation two times perday, wherein the topical formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib, or a pharmaceutically acceptable salt thereof,

-   -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline; and    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a topical formulation two times perday, wherein the topical formulation comprises 0.75% (w/w) on a freebase basis of ruxolitinib phosphate,

-   -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline; and    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a topical formulation two times perday, wherein the topical formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline; and    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein the cream formulation comprises 0.75% (w/w) or 1.5% (w/w)on a free base basis of ruxolitinib, or a pharmaceutically acceptablesalt thereof,

-   -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline; and    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein the cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib, or a pharmaceutically acceptable salt thereof,

-   -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline; and    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein the cream formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib, or a pharmaceutically acceptable salt thereof,

-   -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline; and    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein the cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline; and    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein the cream formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline; and    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline.

In some embodiments of the embodiments in the preceding ten paragraphs,the patient has an Investigator's Global Assessment score of 3 atbaseline. In some embodiments of the embodiments in the preceding tenparagraphs, the patient has an Investigator's Global Assessment score offrom 3 to 4 at baseline. In some embodiments of the embodiments in thepreceding ten paragraphs, the patient has an itch Numerical Rating scaleof score of ≥4 at baseline. In some embodiments of the embodiments inthe preceding ten paragraphs, the patient: has an Investigator's GlobalAssessment score of 3 at baseline; and has an itch Numerical Ratingscale of score of ≥4 at baseline. In some embodiments of the embodimentsin the preceding ten paragraphs, the patient: has an Investigator'sGlobal Assessment score of from 3 to 4 at baseline; and has an itchNumerical Rating scale of score of ≥4 at baseline. In some embodimentsof the embodiments in the preceding ten paragraphs, the patient is aged≥12 years. In some embodiments of the embodiments in the preceding tenparagraphs, the patient has a history of atopic dermatitis for at least2 years. In some embodiments of the embodiments in the preceding tenparagraphs, the patient: has an Investigator's Global Assessment scoreof 3 at baseline; has a history of atopic dermatitis for at least 2years; and is aged ≥12 years. In some embodiments of the embodiments inthe preceding ten paragraphs, the patient: has an Investigator's GlobalAssessment score of from 3 to 4 at baseline; has a history of atopicdermatitis for at least 2 years; and is aged ≥12 years. In someembodiments of the embodiments in the preceding ten paragraphs, thepatient: has an Investigator's Global Assessment score of 3 at baseline;has an itch Numerical Rating scale of score of ≥4 at baseline; has ahistory of atopic dermatitis for at least 2 years; and is aged ≥12years. In some embodiments of the embodiments in the preceding tenparagraphs, the patient: has an Investigator's Global Assessment scoreof from 3 to 4 at baseline; has an itch Numerical Rating scale of scoreof ≥4 at baseline; has a history of atopic dermatitis for at least 2years; and is aged ≥12 years. In some embodiments of the embodiments inthe preceding ten paragraphs, the patient has one or more of thefollowing characteristics: an Investigator's Global Assessment score of3 at baseline; an itch Numerical Rating scale of score of ≥4 atbaseline; a history of atopic dermatitis for at least 2 years; and aged≥12 years. In some embodiments of the embodiments in the preceding tenparagraphs, the patient achieves at least a 4-point reduction in itchNumerical Rating Scale score from baseline. In some embodiments of theembodiments in the preceding ten paragraphs, the patient achieves anInvestigator's Global Assessment score of 0 or 1 with an improvement ofat least 2 points from baseline. In some embodiments of the embodimentsin the preceding ten paragraphs, the patient achieves a statisticallysignificant improvement in Eczema Area and Severity Index score frombaseline. In some embodiments of the embodiments in the preceding tenparagraphs, the patient achieves a 75% improvement in Eczema Area andSeverity Index score from baseline. In some embodiments of theembodiments in the preceding ten paragraphs, the patient achieves atleast a 4-point reduction in itch Numerical Rating Scale score frombaseline; and the patient achieves an Investigator's Global Assessmentscore of 0 or 1 with an improvement of at least 2 points from baseline.In some embodiments of the embodiments in the preceding ten paragraphs,the patient achieves at least a 4-point reduction in itch NumericalRating Scale score from baseline; and the patient achieves a 75%improvement in Eczema Area and Severity Index score from baseline. Insome embodiments of the embodiments in the preceding ten paragraphs, thepatient achieves an Investigator's Global Assessment score of 0 or 1with an improvement of at least 2 points from baseline; and the patientachieves a 75% improvement in Eczema Area and Severity Index score frombaseline. In some embodiments of the embodiments in the preceding tenparagraphs, the patient achieves at least a 4-point reduction in itchNumerical Rating Scale score from baseline; the patient achieves anInvestigator's Global Assessment score of 0 or 1 with an improvement ofat least 2 points from baseline; and the patient achieves a 75%improvement in Eczema Area and Severity Index score from baseline. Insome embodiments of the embodiments in the preceding ten paragraphs, thepatient achieves at least a 4-point reduction in itch Numerical RatingScale score from baseline at week 4 of said administering. In someembodiments of the embodiments in the preceding ten paragraphs, thepatient achieves at least a 4-point reduction in itch Numerical RatingScale score from baseline at week 8 of said administering. In someembodiments of the embodiments in the preceding ten paragraphs, thepatient achieves an Investigator's Global Assessment score of 0 or 1with an improvement of at least 2 points from baseline at week 4 of saidadministering. In some embodiments of the embodiments in the precedingten paragraphs, the patient achieves an Investigator's Global Assessmentscore of 0 or 1 with an improvement of at least 2 points from baselineat week 8 of said administering. In some embodiments of the embodimentsin the preceding ten paragraphs, the patient achieves a 75% improvementin Eczema Area and Severity Index score from baseline at week 4 of saidadministering. In some embodiments of the embodiments in the precedingten paragraphs, the patient achieves a 75% improvement in Eczema Areaand Severity Index score from baseline at week 8 of said administering.In some embodiments of the embodiments in the preceding ten paragraphs,the patient achieves at least a 4-point reduction in itch NumericalRating Scale score from baseline at week 4 of said administering; andthe patient achieves an Investigator's Global Assessment score of 0 or 1with an improvement of at least 2 points from baseline at week 4 of saidadministering. In some embodiments of the embodiments in the precedingten paragraphs, the patient achieves at least a 4-point reduction initch Numerical Rating Scale score from baseline at week 8 of saidadministering; and the patient achieves an Investigator's GlobalAssessment score of 0 or 1 with an improvement of at least 2 points frombaseline at week 8 of said administering. In some embodiments of theembodiments in the preceding ten paragraphs, the patient achieves atleast a 4-point reduction in itch Numerical Rating Scale score frombaseline at week 4 of said administering; and the patient achieves a 75%improvement in Eczema Area and Severity Index score from baseline atweek 4 of said administering. In some embodiments of the embodiments inthe preceding ten paragraphs, the patient achieves at least a 4-pointreduction in itch Numerical Rating Scale score from baseline at week 8of said administering; and the patient achieves a 75% improvement inEczema Area and Severity Index score from baseline at week 8 of saidadministering. In some embodiments of the embodiments in the precedingten paragraphs, the patient achieves an Investigator's Global Assessmentscore of 0 or 1 with an improvement of at least 2 points from baselineat week 4 of said administering; and the patient achieves a 75%improvement in Eczema Area and Severity Index score from baseline atweek 4 of said administering. In some embodiments of the embodiments inthe preceding ten paragraphs, the patient achieves an Investigator'sGlobal Assessment score of 0 or 1 with an improvement of at least 2points from baseline at week 8 of said administering; and the patientachieves a 75% improvement in Eczema Area and Severity Index score frombaseline at week 8 of said administering. In some embodiments of theembodiments in the preceding ten paragraphs, the patient achieves atleast a 4-point reduction in itch Numerical Rating Scale score frombaseline at week 4 of said administering; the patient achieves anInvestigator's Global Assessment score of 0 or 1 with an improvement ofat least 2 points from baseline at week 4 of said administering; and thepatient achieves a 75% improvement in Eczema Area and Severity Indexscore from baseline at week 4 of said administering. In some embodimentsof the embodiments in the preceding ten paragraphs, the patient achievesat least a 4-point reduction in itch Numerical Rating Scale score frombaseline at week 8 of said administering; the patient achieves anInvestigator's Global Assessment score of 0 or 1 with an improvement ofat least 2 points from baseline at week 8 of said administering; and thepatient achieves a 75% improvement in Eczema Area and Severity Indexscore from baseline at week 8 of said administering. In some embodimentsof the embodiments in the preceding ten paragraphs, the administering ismaintained for at least 4 weeks. In some embodiments of the embodimentsin the preceding ten paragraphs, the administering is maintained for atleast 8 weeks.

In some embodiments, the topical formulation is a cream formulation. Insome embodiments, the ruxolitinib or salt thereof is ruxolitinibphosphate. In some embodiments, the formulation comprises 0.75% (w/w) ona free base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises 1.5% (w/w) on afree base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof. In some embodiments, the formulation comprises 0.75% (w/w) on afree base basis of ruxolitinib phosphate. In some embodiments, theformulation comprises 1.5% (w/w) on a free base basis of ruxolitinibphosphate.

In some embodiments, the patient achieves at least a 4 point improvementin improvement in itch Numerical Rating Scale score from baseline. Insome embodiments, the patient achieves at least a 4 point improvement inimprovement in itch Numerical Rating Scale score from baseline, whereinthe patient has a baseline Numerical Rating Scale score of equal to orgreater than 4. In some embodiments, the patient achieves at least a 4point improvement in improvement in itch Numerical Rating Scale scorefrom baseline after 2 weeks of said administering, wherein the patienthas a baseline Numerical Rating Scale score of equal to or greater than4. In some embodiments, the patient achieves at least a 4 pointimprovement in improvement in itch Numerical Rating Scale score frombaseline after 4 weeks of said administering, wherein the patient has abaseline Numerical Rating Scale score of equal to or greater than 4. Insome embodiments, the patient achieves at least a 4 point improvement inimprovement in itch Numerical Rating Scale score from baseline after 8weeks of said administering, wherein the patient has a baselineNumerical Rating Scale score of equal to or greater than 4.

In some embodiments, the patient:

-   -   is aged 18 to 70 years,    -   has been diagnosed with atopic dermatitis for at least 2 years,    -   has an Investigator's Global Assessment score of 2 to 3 at        screening and baseline, and    -   has a BSA of atopic dermatitis involvement (excluding face and        intertriginous areas) of 3% to 20% at baseline.

In some embodiments, the patient:

-   -   is an adolescent aged ≥12 to 17, inclusive, or a man or woman        aged ≥18 years;    -   has history of AD for at least 2 years;    -   has an Investigator's Global Assessment score of 2 to 3 at        baseline; and    -   has a % BSA of AD involvement, excluding the scalp, of 3% to 20%        at baseline.

In some embodiments, the patient:

-   -   is an adolescent aged ≥12 to 17, inclusive, or a man or woman        aged ≥18 years;    -   has history of AD for at least 2 years;    -   has an Investigator's Global Assessment score of 2 to 3 at        baseline;    -   has a % BSA of AD involvement, excluding the scalp, of 3% to 20%        at baseline; and    -   has at least 1 target lesion (which is representative of the        participant's disease state and not present on the hands, feet        or genitalia) that measures about 10 cm² or more at baseline.

In some embodiments, the patient is diagnosed with atopic dermatitis asdefined by the Hanifin and Rajika criteria.

In some embodiments, the patient did not use topical treatments foratopic dermatitis, other than emollients, within 2 weeks of baseline.

In some embodiments, the patient did not use systemic immunosuppressiveor immunomodulating drugs (e.g., oral or injectable corticosteroids,methotrexate, cyclosporine, mycophenolate mofetil, or azathioprine)within 4 weeks or 5 half-lives of baseline (whichever is longer).

In some embodiments, the patient did not use topical treatments foratopic dermatitis, other than bland emollients, within 2 weeks ofbaseline; and did not use systemic immunosuppressive or systemicimmunomodulating drugs within 4 weeks of baseline.

In some embodiments, the patient is not administered other therapeuticagents used to treat atopic dermatitis.

In some embodiments, the patient is not administered systemicimmunosuppressive or systemic immunomodulating drugs or topicaltreatments for atopic dermatitis, other than bland emollients.

In some embodiments, the patient:

-   -   (i) does not show evidence of active acute or chronic        infections; (ii) did not use topical treatments for atopic        dermatitis (other than bland emollients) within 2 weeks of        baseline; (iii) did not use systemic immunosuppressive or        immunomodulating drugs (e.g., oral or injectable        corticosteroids, methotrexate, cyclosporine, mycophenolate        mofetil, or azathioprine) within 4 weeks or 5 half-lives of        baseline (whichever is longer); (iv) was not diagnosed with        other dermatologic disease besides atopic dermatitis whose        presence or treatments could complicate the assessment of        disease; (v) a history of other diseases besides dermatologic        disorders taking treatments that could complicate        assessments; (vi) did not show cytopenias at screening, defined        as leukocytes <3.0×10⁹/L, neutrophils <lower limit of normal,        hemoglobin <10 g/dL. Lymphocytes <0.8×109/L, platelets        <100×109/L; (vii) did not have severely impaired liver function        (Child-Pugh Class C) or end-stage renal disease on dialysis or        at least 1 of the following: serum creatinine >1.5 mg/dL,        alanine aminotransferase or aspartate aminotransferase        ≥1.5×upper limit of normal; (viii) was not taking potent        systemic cytochrome P450 3A4 inhibitors or fluconazole within 2        weeks or 5 half-lives, whichever is longer, before the baseline        visit, other than topical agents with limited systemic        availability; and/or (ix) were not administered Janus kinase        inhibitors, systemic or topical.

In some embodiments, the patient:

-   -   (i) is an adolescent aged ≥12 to 17, inclusive, or a man or        woman aged ≥18 years; (ii) is diagnosed with AD as defined by        the Hanifin and Rajka criteria; (iii) has history of AD for at        least 2 years; (iv) has an Investigator's Global Assessment        score of 2 to 3 at baseline; (v) has a % BSA of AD involvement,        excluding the scalp, of 3% to 20% at baseline; (vi) agreed to        discontinue all agents used to treat AD during the        administering; and/or (vi) has at least 1 target lesion (which        is representative of the participant's disease state and not        present on the hands, feet or genitalia) that measures about 10        cm² or more at baseline.

In some embodiments, the patient:

-   -   (i) does not have an unstable course of AD (spontaneously        improving or rapidly deteriorating) as determined by a physician        in the 4 weeks prior to baseline; (ii) does not have concurrent        conditions and history of other diseases: (a) Immunocompromised        (e.g., lymphoma, acquired immunodeficiency syndrome,        Wiskott-Aldrich syndrome); (b) chronic or acute infection        requiring treatment with systemic antibiotics, antivirals,        antiparasitics, antiprotozoals, or antifungals within 2 weeks        before baseline; (c) active acute bacterial, fungal, or viral        skin infection (e.g., herpes simplex, herpes zoster, chicken        pox) within 1 week before baseline; (d) any other concomitant        skin disorder (e.g., generalized erythroderma such as Netherton        syndrome), pigmentation, or extensive scarring that, in the        opinion of the investigator, may interfere with the evaluation        of AD lesions or compromise participant safety; (e) presence of        AD lesions only on the hands or feet without prior history of        involvement of other classical areas of involvement such as the        face or the folds; (f) other types of eczema; (iii) does not        have any serious illness or medical, physical, or psychiatric        condition(s) that, in the investigator's opinion, would        interfere with full participation in the study, including        administration of study drug and attending required study        visits; pose a significant risk to the participant; or interfere        with interpretation of study data. For example: (a) clinically        significant or uncontrolled cardiac disease, including unstable        angina, acute myocardial infarction within 6 months from Day 1        of study drug administration, New York Heart Association Class        III or IV congestive heart failure, and arrhythmia requiring        therapy or uncontrolled hypertension (blood pressure >150/90        mmHg) unless approved by medical monitor/sponsor; (b)        participants with a history of malignancy in the 5 years        preceding enrollment into this study, except for adequately        treated, nonmetastatic malignancies; (c) low hemoglobin (<10        g/dL); (d) severe renal disease on dialysis (serum creatinine >2        mg/dL); (e) current and/or liver disease history, including        known hepatitis B or C, with hepatic or biliary        abnormalities; (iv) does not receive any of the following        treatments within the indicated washout period before        baseline: (a) 5 half-lives or 12 weeks, whichever is        longer—biologic agents (e.g., dupilumab); (b) 4 weeks—systemic        corticosteroids or adrenocorticotropic hormone analogs,        cyclosporin, methotrexate, azathioprine, or other systemic        immunosuppressive or immunomodulating agents (e.g.,        mycophenolate or tacrolimus); (c) 2 weeks—immunizations and        sedating antihistamines, unless on long-term stable regimen        (nonsedating antihistamines are permitted); (d) 1 week—use of        other topical treatments for AD (other than bland emollients),        such as corticosteroids, calcineurin inhibitors, coal tar        (shampoo), antibiotics, antibacterial cleansing body wash/soap.        Diluted sodium hypochlorite “bleach” baths are allowed as long        as they do not exceed 2 baths per week and their frequency        remains the same throughout the study; (v) has not previously        received JAK inhibitors, systemic or topical; (vi) has not had        ultraviolet light therapy or prolonged exposure to natural or        artificial sources of UV radiation (e.g., sunlight or tanning        booth) within 2 weeks prior to baseline and/or intention to have        such exposure during the study, which is thought by the        investigator to potentially impact the participant's AD; (vii)        does not have positive serology test results at screening for        HIV antibody; (viii) does not have liver function tests with the        following: AST or ALT≥2×ULN; alkaline phosphatase and/or        bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is acceptable if        bilirubin is fractionated and direct bilirubin <35%); (ix) is        not pregnant or lactating, or considering pregnancy; (x) does        not have a history of alcoholism or drug addiction within 1 year        before screening or current alcohol or drug use that, in the        opinion of the investigator, will interfere with the        participant's ability to comply with the administration schedule        and study assessments; and/or (xi) is not currently receiving        treatment or had treatment within 30 days or 5 half-lives        (whichever is longer) before baseline with another        investigational medication or current enrollment in another        investigational drug protocol.

In some embodiments, the two administrations per day are at least 8hours apart.

In some embodiments, the cream formulation is an oil-in-water emulsioncomprising said ruxolitinib, or pharmaceutically acceptable saltthereof.

In some embodiments, the cream formulation is an oil-in-water emulsioncomprising said 1.5% (w/w) on a free base basis of ruxolitinibphosphate.

In some embodiments, the cream formulation is an oil-in-water emulsioncomprising said 0.75% (w/w) on a free base basis of ruxolitinibphosphate.

In some embodiments, the cream formulation has a pH from about 2.8 toabout 3.9.

In some embodiments, the cream formulation has a pH from about 2.8 toabout 3.6.

In some embodiments, the cream formulation is a solubilized cream.

In some embodiments, the administering of the cream formulation does notresult in a statistically significant reduction in hemoglobin orplatelets. In some embodiments, the administering of the creamformulation does not result in administration site burn. In someembodiments, the administering of the cream formulation does not resultin administration site pruritus.

In some embodiments, the patient achieves a prompt reduction of itch.

In some embodiments, the patient achieves a statistically significantreduction of itch at day 1 (i.e., within 12 hours) of saidadministering. In some embodiments, the patient achieves a statisticallysignificant reduction of itch at day 1 (i.e., within 12 hours) of saidadministering of the cream formulation comprising 1.5% (w/w)ruxolitinib, or a pharmaceutically acceptable salt thereof.

In some embodiments, the patient achieves a statistically significantreduction in itch Numerical Rating Scale score from baseline at day 2 ofsaid administering compared to a patient administered placebo for thesame period.

In some embodiments, the patient achieves a statistically significantreduction in itch Numerical Rating Scale score from baseline at day 1 ofsaid administering compared to a patient administered placebo for thesame period.

In some embodiments, the patient achieves at least a 1-point reductionin itch Numerical Rating Scale score from baseline at day 1 of saidadministering.

In some embodiments, the patient achieves at least a 2 point improvementin itch Numerical Rating Scale score from baseline at day 1 of saidadministering.

In some embodiments, the patient achieves at least a 1.5 point reductionin itch Numerical Rating Scale score from baseline at day 1 of saidadministering.

In some embodiments, the patient achieves at least a 1-point reductionin itch Numerical Rating Scale score from baseline at day 2 of saidadministering.

In some embodiments, the patient achieves at least a 1.5 point reductionin itch Numerical Rating Scale score from baseline at day 2 of saidadministering.

In some embodiments, the patient achieves at least a 2 point reductionin itch Numerical Rating Scale score from baseline at day 2 of saidadministering.

In some embodiments, the patient achieves at least a 2 point reductionin itch Numerical Rating Scale score from baseline at day 4 of saidadministering.

In some embodiments, the patient achieves at least a 1 point reductionin itch Numerical Rating Scale score by day 2 of said administering.

In some embodiments, the patient achieves at least a 1 point reductionin itch Numerical Rating Scale score within 36 hours of saidadministering.

In some embodiments, the patient achieves at least a 2 point reductionin itch Numerical Rating Scale score by day 6 of said administering.

In some embodiments, the patient achieves at least a 2 point reductionin itch Numerical Rating Scale score at week 1 of said administering.

In some embodiments, the patient achieves at least a 3 point reductionin itch Numerical Rating Scale score at week 3 of said administering.

In some embodiments, the patient achieves: at least a 1 point reductionin itch Numerical Rating Scale score by day 2 of said administering, atleast a 2 point reduction in itch Numerical Rating Scale score by day 6of said administering and at least a 3 point reduction in itch NumericalRating Scale score at week 3 of said administering.

In some embodiments, the patient achieves: at least a 1 point reductionin itch Numerical Rating Scale score within 36 hours of saidadministering, at least a 2 point reduction in itch Numerical RatingScale score by day 6 of said administering and at least a 3 pointreduction in itch Numerical Rating Scale score at week 3 of saidadministering.

In some embodiments, the patient achieves: at least a 1 point reductionin itch Numerical Rating Scale score by day 2 of said administering, atleast a 2 point reduction in itch Numerical Rating Scale score at week 1of said administering, and at least a 3 point reduction in itchNumerical Rating Scale score at week 3 of said administering.

In some embodiments, the patient achieves: at least a 1 point reductionin itch Numerical Rating Scale score within 36 hours of saidadministering, at least a 2 point reduction in itch Numerical RatingScale score at week 1 of said administering, and at least a 3 pointreduction in itch Numerical Rating Scale score at week 3 of saidadministering.

A method of reducing itch in a human patient with atopic dermatitis,comprising administering to the skin of said human patient in needthereof, a cream formulation two times per day, wherein said creamformulation comprises 1.5% (w/w) on a free base basis of ruxolitinib, ora pharmaceutically acceptable salt thereof, wherein the patient achievesat least a 1 point reduction in itch Numerical Rating Scale score by day2 of said administering.

A method of reducing itch in a human patient with atopic dermatitis,comprising administering to the skin of said human patient in needthereof, a cream formulation two times per day, wherein said creamformulation comprises 1.5% (w/w) on a free base basis of ruxolitinib, ora pharmaceutically acceptable salt thereof, wherein the patient achievesat least a 1 point reduction in itch Numerical Rating Scale score within36 hours of said administering.

A method of reducing itch in a human patient with atopic dermatitis,comprising administering to the skin of said human patient in needthereof, a cream formulation two times per day, wherein said creamformulation comprises 1.5% (w/w) on a free base basis of ruxolitinib, ora pharmaceutically acceptable salt thereof, wherein the patient achievesat least a 2 point reduction in itch Numerical Rating Scale score by day6 of said administering.

A method of reducing itch in a human patient with atopic dermatitis,comprising administering to the skin of said human patient in needthereof, a cream formulation two times per day, wherein said creamformulation comprises 1.5% (w/w) on a free base basis of ruxolitinib, ora pharmaceutically acceptable salt thereof, wherein the patient achievesat least a 2 point reduction in itch Numerical Rating Scale score atweek 1 of said administering.

A method of reducing itch in a human patient with atopic dermatitis,comprising administering to the skin of said human patient in needthereof, a cream formulation two times per day, wherein said creamformulation comprises 1.5% (w/w) on a free base basis of ruxolitinib, ora pharmaceutically acceptable salt thereof, wherein the patient achievesat least a 3 point reduction in itch Numerical Rating Scale score atweek 3 of said administering.

A method of reducing itch in a human patient with atopic dermatitis,comprising administering to the skin of said human patient in needthereof, a cream formulation two times per day, wherein said creamformulation comprises 1.5% (w/w) on a free base basis of ruxolitinib, ora pharmaceutically acceptable salt thereof, wherein the patientachieves: at least a 1 point reduction in itch Numerical Rating Scalescore by day 2 of said administering, at least a 2 point reduction initch Numerical Rating Scale score by day 6 of said administering and atleast a 3 point reduction in itch Numerical Rating Scale score at week 3of said administering.

A method of reducing itch in a human patient with atopic dermatitis,comprising administering to the skin of said human patient in needthereof, a cream formulation two times per day, wherein said creamformulation comprises 1.5% (w/w) on a free base basis of ruxolitinib, ora pharmaceutically acceptable salt thereof, wherein the patientachieves: at least a 1 point reduction in itch Numerical Rating Scalescore within 36 hours of said administering, at least a 2 pointreduction in itch Numerical Rating Scale score by day 6 of saidadministering and at least a 3 point reduction in itch Numerical RatingScale score at week 3 of said administering.

A method of reducing itch in a human patient with atopic dermatitis,comprising administering to the skin of said human patient in needthereof, a cream formulation two times per day, wherein said creamformulation comprises 1.5% (w/w) on a free base basis of ruxolitinib, ora pharmaceutically acceptable salt thereof, wherein the patientachieves: at least a 1 point reduction in itch Numerical Rating Scalescore by day 2 of said administering, at least a 2 point reduction initch Numerical Rating Scale score at week 1 of said administering, andat least a 3 point reduction in itch Numerical Rating Scale score atweek 3 of said administering.

A method of reducing itch in a human patient with atopic dermatitis,comprising administering to the skin of said human patient in needthereof, a cream formulation two times per day, wherein said creamformulation comprises 1.5% (w/w) on a free base basis of ruxolitinib, ora pharmaceutically acceptable salt thereof, wherein the patientachieves: at least a 1 point reduction in itch Numerical Rating Scalescore within 36 hours of said administering, at least a 2 pointreduction in itch Numerical Rating Scale score at week 1 of saidadministering, and at least a 3 point reduction in itch Numerical RatingScale score at week 3 of said administering.

In some embodiments, the patient achieves a minimal clinically importantdifference in itch Numerical Rating Scale score at day 1 of saidadministering.

In some embodiments, the patient achieves a minimal clinically importantdifference in itch Numerical Rating Scale score at day 2 of saidadministering.

In some embodiments, the patient achieves a minimal clinically importantdifference in itch Numerical Rating Scale score at day 3 of saidadministering.

In some embodiments, the patient achieves a minimal clinically importantdifference in itch Numerical Rating Scale score at day 4 of saidadministering.

In some embodiments, the patient achieves a clinically relevantimprovement in itch Numerical Rating Scale score at day 2 of saidadministering.

In some embodiments, the patient achieves a clinically relevantimprovement in itch Numerical Rating Scale score at day 3 of saidadministering.

In some embodiments, the patient achieves a clinically relevantimprovement in itch Numerical Rating Scale score at day 4 of saidadministering.

In some embodiments, the patient achieves a statistically significantreduction in itch Numerical Rating Scale score from baseline at week 2of said administering compared to a patient administered placebo for thesame period.

In some embodiments, the patient achieves at least a 3 point reductionin itch Numerical Rating Scale score from baseline at week 2 of saidadministering.

In some embodiments, the patient achieves a clinically relevantimprovement in itch Numerical Rating Scale score at week 2 of saidadministering.

In some embodiments, the patient achieves a statistically significantreduction in itch Numerical Rating Scale score from baseline at week 4of said administering compared to a patient administered placebo for thesame period.

In some embodiments, the patient achieves at least a 3 point reductionin itch Numerical Rating Scale score from baseline at week 4 of saidadministering.

In some embodiments, the patient achieves a clinically relevantimprovement in itch Numerical Rating Scale score at week 4 of saidadministering.

In some embodiments, the patient achieves a statistically significantreduction in itch Numerical Rating Scale score from baseline at week 8of said administering compared to a patient administered placebo for thesame period.

In some embodiments, the patient achieves at least a 3 point reductionin itch Numerical Rating Scale score from baseline at week 8 of saidadministering.

In some embodiments, the patient achieves at least a 4 point reductionin itch Numerical Rating Scale score from baseline at week 8 of saidadministering.

In some embodiments, the patient achieves a clinically relevantimprovement in itch Numerical Rating Scale score at week 8 of saidadministering.

In some embodiments, the patient achieves at least a 4.5 point reductionin itch Numerical Rating Scale score from baseline at week 12 of saidadministering.

In some embodiments, the administering reverses the symptomatology ofatopic dermatitis.

In some embodiments, the patient achieves a statistically significantimprovement in Eczema Area and Severity Index score from baseline atweek 4 of said administering compared to a patient administered placebofor the same period.

In some embodiments, the patient achieves a statistically significantimprovement in Eczema Area and Severity Index score from baseline atweek 8 of said administering compared to a patient administered placebofor the same period.

In some embodiments, the patient achieves a 75% improvement in EczemaArea and Severity Index score from baseline at week 2 of saidadministering.

In some embodiments, the patient achieves a 75% improvement in EczemaArea and Severity Index score from baseline at week 4 of saidadministering.

In some embodiments, the patient achieves a 75% improvement in EczemaArea and Severity Index score from baseline at week 8 of saidadministering.

In some embodiments, the patient achieves a 75% improvement in EczemaArea and Severity Index score from baseline at week 12 of saidadministering.

In some embodiments, the patient achieves an Investigator's GlobalAssessment score of 0 or 1 with an improvement of at least 2 points frombaseline at 2 weeks of said administering.

In some embodiments, the patient achieves an Investigator's GlobalAssessment score of 0 or 1 with an improvement of at least 2 points frombaseline at 4 weeks of said administering.

In some embodiments, the patient achieves an Investigator's GlobalAssessment score of 0 or 1 with an improvement of at least 2 points frombaseline at 8 weeks of said administering.

In some embodiments, the patient achieves a clinically meaningfulimprovement in the PROMIS Short Form—Sleep Disturbances (8b) 24-hourrecall score at Week 8.

In some embodiments, the patient achieves at least a 50% improvement inSkindex-16 overall score at week 2 of said administering.

In some embodiments, the patient achieves at least a 60% improvement inSkindex-16 overall score at week 2 of said administering.

In some embodiments, the patient achieves at least a 50% improvement inSkindex-16 overall score at week 4 of said administering.

In some embodiments, the patient achieves at least a 60% improvement inSkindex-16 overall score at week 4 of said administering.

In some embodiments, the patient achieves at least a 70% improvement inSkindex-16 overall score at week 4 of said administering.

In some embodiments, the patient achieves at least a 50% improvement inSkindex-16 overall score at week 8 of said administering.

In some embodiments, the patient achieves at least a 60% improvement inSkindex-16 overall score at week 8 of said administering.

In some embodiments, the patient achieves at least a 70% improvement inSkindex-16 overall score at week 8 of said administering.

In some embodiments, the patient is suffering from mild to moderateatopic dermatitis.

In some embodiments, the administering is maintained for at least 2weeks.

In some embodiments, the administering is maintained for at least 4weeks.

In some embodiments, the administering is maintained for at least 8weeks.

In some embodiments, the administering is maintained for at least 12weeks.

The present disclosure also provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 1.5% (w/w) on a free base basis of ruxolitinibphosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of the        administering.

The present disclosure further provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 0.75% (w/w) on a free base basis of ruxolitinibphosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of the        administering.

The present disclosure also provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 1.5% (w/w) on a free base basis of ruxolitinibphosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of the        administering, and    -   wherein the patient:    -   is aged 18 to 70 years,    -   has been diagnosed with atopic dermatitis for at least 2 years,    -   has an Investigator's Global Assessment score of 2 to 3 at        screening and baseline, and    -   has a Body Surface Area of atopic dermatitis involvement        (excluding face and intertriginous areas) of 3% to 20% at        baseline.

The present disclosure further provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 0.75% (w/w) or 1.5% (w/w) on a free base basis ofruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of the        administering, and    -   wherein the patient:    -   is an adolescent aged ≥12 to 17, inclusive, or a man or woman        aged ≥18 years;    -   has history of AD for at least 2 years;    -   has an Investigator's Global Assessment score of 2 to 3 at        baseline; and    -   has a % BSA of AD involvement, excluding the scalp, of 3% to 20%        at baseline.

The present disclosure also provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 1.5% (w/w) on a free base basis of ruxolitinibphosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering, and    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering.

The present disclosure also provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 0.75% (w/w) or 1.5% (w/w) on a free base basis ofruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering, and    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering.

The present disclosure further provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 1.5% (w/w) on a free base basis of ruxolitinibphosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4-point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein the patient:    -   is aged 18 to 70 years,    -   has been diagnosed with atopic dermatitis for at least 2 years,    -   has an Investigator's Global Assessment score of 2 to 3 at        screening and baseline, and    -   has a BSA of atopic dermatitis involvement (excluding face and        intertriginous areas) of 3% to 20% at baseline.

The present disclosure further provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation is an oil-in-wateremulsion, comprising 0.75% (w/w) or 1.5% (w/w) on a free base basis ofruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein the patient:    -   is an adolescent aged ≥12 to 17, inclusive, or a man or woman        aged ≥18 years;    -   has history of AD for at least 2 years;    -   has an Investigator's Global Assessment score of 2 to 3 at        baseline; and    -   has a % BSA of AD involvement, excluding the scalp, of 3% to 20%        at baseline.

In another embodiment, the present disclosure provides a method ofreducing itch in a human patient with atopic dermatitis, comprisingadministering two times a day to the skin of said human patient in needthereof, a composition comprising:

-   -   (1) 1.5% (w/w) on a free base basis of ruxolitinib phosphate,        and    -   (2) means for effecting dose-dependent skin permeation of said        ruxolitinib phosphate, wherein said patient achieves a reduction        in the itch Numerical Rating Scale score from baseline.

In another embodiment, the present disclosure provides a method ofreducing itch in a human patient with atopic dermatitis, comprisingadministering two times a day to the skin of said human patient in needthereof, a composition comprising:

-   -   (1) 0.75% (w/w) on a free base basis of ruxolitinib phosphate,        and    -   (2) means for effecting dose-dependent skin permeation of said        ruxolitinib phosphate, wherein said patient achieves a reduction        in the itch Numerical Rating Scale score from baseline.

The present disclosure also provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 1.5% (w/w) on afree base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof,

-   -   wherein said patient achieves a reduction in the itch Numerical        Rating Scale score from baseline.

The present disclosure also provides a method of reducing itch in ahuman patient with atopic dermatitis, comprising administering to theskin of said human patient in need thereof, a cream formulation twotimes per day, wherein said cream formulation comprises 0.75% (w/w) on afree base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof,

-   -   wherein said patient achieves a reduction in the itch Numerical        Rating Scale score from baseline.

The present disclosure further provides a method of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) or 1.5% (w/w)on a free base basis of ruxolitinib, or a pharmaceutically acceptablesalt thereof;

-   -   wherein said patient has one or more characteristics selected        from the group consisting of:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline; and    -   an Investigator's Global Assessment score of at least 3 at        baseline.

The present disclosure also provides a method of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib, or a pharmaceutically acceptable salt thereof;

-   -   wherein said patient has one or more characteristics selected        from the group consisting of:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline; and    -   an Investigator's Global Assessment score of at least 3 at        baseline.

The present disclosure further provides a method of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib, or a pharmaceutically acceptable salt thereof;

-   -   wherein said patient has one or more characteristics selected        from the group consisting of:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline; and    -   an Investigator's Global Assessment score of at least 3 at        baseline.

The present disclosure also provides a method of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib phosphate;

-   -   wherein said patient has one or more characteristics selected        from the group consisting of:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline; and    -   an Investigator's Global Assessment score of at least 3 at        baseline.

The present disclosure further provides a method of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib phosphate;

-   -   wherein said patient has one or more characteristics selected        from the group consisting of:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline; and    -   an Investigator's Global Assessment score of at least 3 at        baseline.

In some embodiments, the patient has one or more characteristicsselected from the group consisting of:

-   -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline;    -   an Investigator's Global Assessment score of ≥3 at baseline;    -   an age between 12 to 85 years; and    -   a history of atopic dermatitis for at least 2 years.

In some embodiments, the patient has one or more characteristicsselected from the group consisting of:

-   -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline; and    -   an Investigator's Global Assessment score of 3 at baseline.

In some embodiments, the patient has an Eczema Area and Severity Indexscore of ≥16 at baseline.

In some embodiments, the patient has a Body Surface Area of atopicdermatitis involvement of ≥10% at baseline.

In some embodiments, the patient has a Body Surface Area of atopicdermatitis involvement of from 10% to 20% at baseline.

In some embodiments, the patient has an itch Numerical Rating Scalescore of ≥4 at baseline.

In some embodiments, the patient has an Investigator's Global Assessmentscore of 3 at baseline.

In some embodiments, the patient is suffering from moderate atopicdermatitis.

In some embodiments, the patient is suffering from moderate to severeatopic dermatitis.

In some embodiments, the patient has an Eczema Area and Severity Indexof ≥16 at baseline and a Body Surface Area of atopic dermatitisinvolvement of ≥10% at baseline. In some embodiments of the embodimentsof this paragraph, the Body Surface Area of atopic dermatitisinvolvement is alternatively from 10% to 20% at baseline.

In some embodiments, the patient has an Eczema Area and Severity Indexscore of ≥16 at baseline, a Body Surface Area of atopic dermatitisinvolvement of ≥10% at baseline, and an itch Numerical Rating Scalescore of ≥4 at baseline. In some embodiments of the embodiments of thisparagraph, the Body Surface Area of atopic dermatitis involvement isalternatively from 10% to 20% at baseline.

In some embodiments, the patient, who has an Eczema Area and SeverityIndex score of ≥16 at baseline and a Body Surface Area of atopicdermatitis involvement of ≥10% at baseline, achieves a 75% improvementin Eczema Area and Severity Index score from baseline at week 2 of saidadministering. In some embodiments of the embodiments of this paragraph,the Body Surface Area of atopic dermatitis involvement is alternativelyfrom 10% to 20% at baseline.

In some embodiments, the patient, who has an Eczema Area and SeverityIndex score of ≥16 at baseline and a Body Surface Area of atopicdermatitis involvement of ≥10% at baseline, achieves a 75% improvementin Eczema Area and Severity Index score from baseline at week 4 of saidadministering. In some embodiments of the embodiments of this paragraph,the Body Surface Area of atopic dermatitis involvement is alternativelyfrom 10% to 20% at baseline.

In some embodiments, the patient, who has an Eczema Area and SeverityIndex score of ≥16 at baseline and a Body Surface Area of atopicdermatitis involvement of ≥10% at baseline, achieves a 75% improvementin Eczema Area and Severity Index score from baseline at week 8 of saidadministering. In some embodiments of the embodiments of this paragraph,the Body Surface Area of atopic dermatitis involvement is alternativelyfrom 10% to 20% at baseline.

In some embodiments, the patient who has an Eczema Area and SeverityIndex score of ≥16 at baseline and a Body Surface Area of atopicdermatitis involvement of ≥10% at baseline, achieves an Investigator'sGlobal Assessment score of 0 or 1 with an improvement of at least 2points from baseline at 2 weeks of said administering. In someembodiments of the embodiments of this paragraph, the Body Surface Areaof atopic dermatitis involvement is alternatively from 10% to 20% atbaseline.

In some embodiments, the patient, who has an Eczema Area and SeverityIndex score of ≥16 at baseline and a Body Surface Area of atopicdermatitis involvement of ≥10% at baseline, achieves an Investigator'sGlobal Assessment score of 0 or 1 with an improvement of at least 2points from baseline at 4 weeks of said administering. In someembodiments of the embodiments of this paragraph, the Body Surface Areaof atopic dermatitis involvement is alternatively from 10% to 20% atbaseline.

In some embodiments, the patient, who has an Eczema Area and SeverityIndex score of ≥16 at baseline and a Body Surface Area of atopicdermatitis involvement of ≥10% at baseline, achieves an Investigator'sGlobal Assessment score of 0 or 1 with an improvement of at least 2points from baseline at 8 weeks of said administering. In someembodiments of the embodiments of this paragraph, the Body Surface Areaof atopic dermatitis involvement is alternatively from 10% to 20% atbaseline.

In some embodiments, the patient has an Eczema Area and Severity Indexscore of ≥16 at baseline and a Body Surface Area of atopic dermatitisinvolvement of ≥10% at baseline, achieves at least a 4-point reductionin itch Numerical Rating Scale score from baseline at week 2 of saidadministering. In some embodiments of the embodiments of this paragraph,the Body Surface Area of atopic dermatitis involvement is alternativelyfrom 10% to 20% at baseline.

In some embodiments, the patient has an Eczema Area and Severity Indexscore of ≥16 at baseline; a Body Surface Area of atopic dermatitisinvolvement of ≥10% at baseline, achieves at least a 4-point reductionin itch Numerical Rating Scale score from baseline at week 4 of saidadministering. In some embodiments of the embodiments of this paragraph,the Body Surface Area of atopic dermatitis involvement is alternativelyfrom 10% to 20% at baseline.

In some embodiments, the patient, who has an Eczema Area and SeverityIndex score of ≥16 at baseline and a Body Surface Area of atopicdermatitis involvement of ≥10% at baseline, achieves at least a 4-pointreduction in itch Numerical Rating Scale score from baseline at week 8of said administering. In some embodiments of the embodiments of thisparagraph, the Body Surface Area of atopic dermatitis involvement isalternatively from 10% to 20% at baseline.

In some embodiments, the patient, who has an Eczema Area and SeverityIndex score of ≥16 at baseline, a Body Surface Area of atopic dermatitisinvolvement of ≥10% at baseline, and an itch Numerical Rating Scalescore of ≥4 at baseline, achieves at least a 4 point reduction in itchNumerical Rating Scale score from baseline at week 2 of saidadministering. In some embodiments of the embodiments of this paragraph,the Body Surface Area of atopic dermatitis involvement is alternativelyfrom 10% to 20% at baseline.

In some embodiments, the patient, who has an Eczema Area and SeverityIndex score of ≥16 at baseline, a Body Surface Area of atopic dermatitisinvolvement of ≥10% at baseline, and an itch Numerical Rating Scalescore of ≥4 at baseline, achieves at least a 4 point reduction in itchNumerical Rating Scale score from baseline at week 4 of saidadministering. In some embodiments of the embodiments of this paragraph,the Body Surface Area of atopic dermatitis involvement is alternativelyfrom 10% to 20% at baseline.

In some embodiments, the patient, who has an Eczema Area and SeverityIndex score of ≥16 at baseline, a Body Surface Area of atopic dermatitisinvolvement of ≥10% at baseline, and an itch Numerical Rating Scalescore of ≥4 at baseline, achieves at least a 4 point reduction in itchNumerical Rating Scale score from baseline at week 8 of saidadministering. In some embodiments of the embodiments of this paragraph,the Body Surface Area of atopic dermatitis involvement is alternativelyfrom 10% to 20% at baseline.

In some embodiments, the patient has an Eczema Area and Severity Indexscore of ≥16 at baseline, a Body Surface Area of atopic dermatitisinvolvement of ≥10% at baseline, and an Investigator's Global Assessmentscore of ≥3 at screening and baseline visits. In some embodiments of theembodiments of this paragraph, the Body Surface Area of atopicdermatitis involvement is alternatively from 10% to 20% at baseline.

In some embodiments, the patient has an Eczema Area and Severity Indexscore of ≥16 at baseline, a Body Surface Area of atopic dermatitisinvolvement of ≥10% at baseline, and an Investigator's Global Assessmentscore of 3 at screening and baseline visits. In some embodiments of theembodiments of this paragraph, the Body Surface Area of atopicdermatitis involvement is alternatively from 10% to 20% at baseline.

In some embodiments, the patient has characteristics comprising: anEczema Area and Severity Index score of ≥16 at baseline; a Body SurfaceArea of atopic dermatitis involvement of ≥10% at baseline; an agebetween 12 to 85 years; and a history of atopic dermatitis for at least2 years. In some embodiments, the characteristics further comprise anInvestigator's Global Assessment score of ≥3 at screening and baselinevisits. In some embodiments, the characteristics further comprise anInvestigator's Global Assessment score of 3 at screening and baselinevisits. In some embodiments, the characteristics further comprise anitch Numerical Rating Scale score of ≥4 at baseline. In some embodimentsof the embodiments of this paragraph, the Body Surface Area of atopicdermatitis involvement is alternatively from 10% to 20% at baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4-point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein said patient has one or more characteristics selected        from the group consisting of:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline;    -   an Investigator's Global Assessment score of at least 3 at        baseline;    -   aged ≥12 years; and    -   a history of atopic dermatitis for at least 2 years.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4-point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein said patient has characteristics comprising:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   aged ≥12 years; and    -   a history of atopic dermatitis for at least 2 years.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4-point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein said patient has characteristics comprising:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline;    -   aged ≥12 years; and    -   a history of atopic dermatitis for at least 2 years.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4-point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein said patient has:    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline;    -   an Investigator's Global Assessment score of at least 3 at        baseline;    -   aged ≥12 years; and    -   a history of atopic dermatitis for at least 2 years.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 0.75% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4-point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline;    -   an Investigator's Global Assessment score of 3 at screening and        baseline visits;    -   aged ≥12 years; and    -   a history of atopic dermatitis for at least 2 years.

In another embodiment, the present disclosure provides a method oftreating atopic dermatitis in a human patient with atopic dermatitis,comprising administering two times a day to the skin of said humanpatient in need thereof, a composition comprising:

-   -   (1) 0.75% (w/w) on a free base basis of ruxolitinib phosphate,        and    -   (2) means for effecting dose-dependent skin permeation of said        ruxolitinib phosphate, wherein said patient achieves IGA        treatment success.

In another embodiment, the present disclosure provides a method oftreating atopic dermatitis in a human patient with atopic dermatitis,comprising administering two times a day to the skin of said humanpatient in need thereof, a composition comprising:

-   -   (1) 0.75% (w/w) on a free base basis of ruxolitinib phosphate,        and    -   (2) means for effecting dose-dependent skin permeation of said        ruxolitinib phosphate, wherein said patient achieves EASI-75.

In another embodiment, the present disclosure provides a method oftreating atopic dermatitis in a human patient with atopic dermatitis,comprising administering two times a day to the skin of said humanpatient in need thereof, a composition comprising:

-   -   (1) 0.75% (w/w) on a free base basis of ruxolitinib phosphate,        and    -   (2) means for effecting dose-dependent skin permeation of said        ruxolitinib phosphate, wherein said patient achieves a reduction        in the itch Numerical Rating Scale score from baseline.

In another embodiment, the present disclosure provides a method oftreating atopic dermatitis in a human patient with atopic dermatitis,comprising administering two times a day to the skin of said humanpatient in need thereof, a composition comprising:

-   -   (1) 0.75% (w/w) on a free base basis of ruxolitinib phosphate,        and    -   (2) means for effecting dose-dependent skin permeation of said        ruxolitinib phosphate, wherein said patient achieves at least a        4-point improvement in improvement in itch Numerical Rating        Scale score from baseline.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4 point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein said patient has one or more characteristics selected        from the group consisting of:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline;    -   an Investigator's Global Assessment score of ≥3 at screening and        baseline visits;    -   aged ≥12 years; and    -   a history of atopic dermatitis for at least 2 years.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4-point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein said patient has characteristics comprising:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   aged ≥12 years; and    -   a history of atopic dermatitis for at least 2 years.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises or 1.5% (w/w) on a freebase basis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4-point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein said patient has characteristics comprising:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline;    -   aged ≥12 years; and    -   a history of atopic dermatitis for at least 2 years.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4-point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline;    -   an Investigator's Global Assessment score of at least 3 at        screening and baseline visits;    -   aged ≥12 years; and    -   a history of atopic dermatitis for at least 2 years.

The present disclosure further provides methods of treating atopicdermatitis in a human patient comprising administering to the skin ofsaid human patient in need thereof, a cream formulation two times perday, wherein said cream formulation comprises 1.5% (w/w) on a free basebasis of ruxolitinib phosphate,

-   -   wherein the administering is maintained for at least 8 weeks,    -   wherein the patient achieves at least a 4-point reduction in        itch Numerical Rating Scale score from baseline at week 8 of        said administering,    -   wherein the patient achieves an Investigator's Global Assessment        score of 0 or 1 with an improvement of at least 2 points from        baseline at 8 weeks of said administering, and    -   wherein said patient has:    -   an Eczema Area and Severity Index score of ≥16 at baseline;    -   a Body Surface Area of atopic dermatitis involvement of ≥10% at        baseline;    -   an itch Numerical Rating Scale score of ≥4 at baseline;    -   an Investigator's Global Assessment score of 3 at screening and        baseline visits;    -   aged ≥12 years; and    -   a history of atopic dermatitis for at least 2 years.

In another embodiment, the present disclosure provides a method oftreating atopic dermatitis in a human patient with atopic dermatitis,comprising administering two times a day to the skin of said humanpatient in need thereof, a composition comprising:

-   -   (1) 1.5% (w/w) on a free base basis of ruxolitinib phosphate,        and    -   (2) means for effecting dose-dependent skin permeation of said        ruxolitinib phosphate, wherein said patient achieves IGA        treatment success.

In another embodiment, the present disclosure provides a method oftreating atopic dermatitis in a human patient with atopic dermatitis,comprising administering two times a day to the skin of said humanpatient in need thereof, a composition comprising:

-   -   (1) 1.5% (w/w) on a free base basis of ruxolitinib phosphate,        and    -   (2) means for effecting dose-dependent skin permeation of said        ruxolitinib phosphate, wherein said patient achieves EASI-75.

In another embodiment, the present disclosure provides a method oftreating atopic dermatitis in a human patient with atopic dermatitis,comprising administering two times a day to the skin of said humanpatient in need thereof, a composition comprising:

-   -   (1) 1.5% (w/w) on a free base basis of ruxolitinib phosphate,        and    -   (2) means for effecting dose-dependent skin permeation of said        ruxolitinib phosphate, wherein said patient achieves a reduction        in the itch Numerical Rating Scale score from baseline.

In another embodiment, the present disclosure provides a method oftreating atopic dermatitis in a human patient with atopic dermatitis,comprising administering two times a day to the skin of said humanpatient in need thereof, a composition comprising:

-   -   (1) 1.5% (w/w) on a free base basis of ruxolitinib phosphate,        and    -   (2) means for effecting dose-dependent skin permeation of said        ruxolitinib phosphate, wherein said patient achieves at least a        4-point improvement in improvement in itch Numerical Rating        Scale score from baseline.

Definitions

As used herein, “ruxolitinib phosphate” means the phosphoric acid saltof ruxolitinib, wherein the ruxolitinib and phosphoric acid are in a 1:1ratio.

In some embodiments, “cream” means an emulsion, semisolid dosage formfor application to the skin.

When the methods refer to “at day 2”, “at week 4”, “at week 8” “at week12”, “within 36 hours”, or “within 12 hours” of the administering, thisrefers to the time period following the first dose of the creamformulation wherein there is no interruption in the administration. Forexample, if the method refers to a reduction in itch NRS score frombaseline at week 8 for a patient administered the cream formulation BID,this means the itch NRS score was assessed after 8 weeks of BIDadministration of the cream formulation following the first dose of thecream formulation with no days being skipped. In terms of itch NRS,because the ruxolitinib cream or vehicle is applied in the morning anditch NRS is measured in the evening (see Phase 2 and Phase 3 studies inthe Examples), “at day 1” means after approximately 12 hours ofadministration, “at day 2” means after approximately 36 hours ofadministration, “at day 3” means after approximately 2.5 days ofadministration, etc.

As used herein, “prompt reduction of itch” means that there is astatistically significant reduction in itch NRS score within 12 hours(or as used herein “at day 1”) of the first administration ofruxolitinib cream as compared to vehicle.

The “Hanifin and Rajika criteria” is described in Hanifin J M, Rajka G.“Diagnostic features of atopic dermatitis,” Acta Derm Venereol Suppl(Stockh) 1980; 92:44-47, which is incorporated herein by reference inits entirety.

As used herein, “% BSA” refers to percentage of total Body Surface Areaaffected by AD. It can be determined to the nearest 0.1% (“handprint”)using, as guides, the palm with fingers as 1% and the thumb as 0.1% forareas identified to be treated with ruxolitinib cream at baseline(excluding face and intertriginous areas; or alternatively, excludingthe scalp).

As used herein, “itch NRS score” refers to itch Numerical Rating Scale.The itch NRS is a daily patient-reported measure (24-hour recall) ofitch intensity. Subjects will be asked to rate the itching severitybecause of their AD by selecting a number from 0 (no itch) to 10 (worstimaginable itch) that best describes their worst level of itching in thepast 24 hours. In a non-limiting example, patients can be issued ahand-held device (eDiary) on which to record itch severity. The patientcan be instructed to complete the eDiary each night.

As used herein “EASI” refers to Eczema Area and Severity Index. The EASIscoring system is a validated disease measurement for clinical studies(Hanifin J M, et al, Exp Dermatol 2001; 10:11-18). The severity stratafor the EASI are as follows: 0=clear; 0.1 to 1.0=almost clear; 1.1 to7.0=mild; 7.1 to 21.0=moderate; 21.1 to 50.0=severe; 50.1 to 72.0=verysevere.

As used herein, “EASI-75” refers to a ≥75% improvement in the patient'sEczema Area and Severity Index.

As used herein, “BID” refers to two times per day.

As used herein, “QD” refers to once per day.

As used herein, “statistically significant” means a p-value of <0.05(preferably <0.001, and most preferably <0.0001).

As used herein, “IGA” refers to Investigator's Global Assessment. Thegrades for IGA are shown in the table below:

Grade Severity Status 0 Clear No inflammatory signs of AD 1 Almost Justperceptible erythema and just perceptible clear papulation/infiltration2 Mild Mild erythema and mild papulation/infiltration disease 3 ModerateModerate erythema and moderate papulation/infiltration disease 4 SevereSevere erythema and severe papulation/infiltration disease 5 Very Severeerythema and severe papulation/infiltration with severe oozing/crustingdisease

As used herein, “IGA-TS” means Investigator's Global AssessmentTreatment Success, which is an IGA score of 0 or 1 with ≥2 gradeimprovement from baseline.

As used herein, the phrase “pharmaceutically acceptable” means thosecompounds, materials, compositions, and/or dosage forms, which are,within the scope of sound medical judgment, suitable for use in contactwith tissues of humans and animals. In some embodiments,“pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopeia orother generally recognized pharmacopeia for use in animals, and moreparticularly in humans.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods. Generally, such salts can be prepared by reacting the free acidor base forms of these compounds with a stoichiometric amount of theappropriate base or acid in water or in an organic solvent, or in amixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile (MeCN) are preferred.Lists of suitable salts are found in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418and Journal of Pharmaceutical Science, 66, 2 (1977), each of which isincorporated herein by reference in its entirety. In some embodiments,the pharmaceutically acceptable salt is a phosphoric acid salt, asulfuric acid salt, or a maleic acid salt.

As used herein, “PROMIS” refers to Patient-Reported Outcomes MeasurementInformation System (PROMIS®), which is a set of widely used and acceptedpatient-reported outcome measurements that have been developed withstrong clinical outcome assessment development methods and arepsychometrically supported. The selected PROMIS Short Form—Sleep-RelatedImpairment (8a) and Short Form—Sleep-Disturbance (8b) questionnaireshave been modified to be completed with a diary on a daily basis with a24-hour recall: Short Form—Sleep-Related Impairment (8a) is collected inthe evening, and Short Form—Sleep-Disturbance (8b) is collected in themorning during the vehicle-control period.

As used herein, “minimal clinically important difference” or “MCID”refers to a 2-3 point reduction in itch NRS versus baseline.

As used herein, “clinically relevant improvement” or “CRI” refers to a≥4 point reduction in itch NRS versus baseline.

As used herein, the term “emulsifier component” refers, in one aspect,to a substance, or mixtures of substances that maintains an element orparticle in suspension within a fluid medium. In some embodiments, theemulsifier component allows an oil phase to form an emulsion whencombined with water. In some embodiments, the emulsifier componentrefers to one or more non-ionic surfactants.

As used herein, the term “occlusive agent component” refers to ahydrophobic agent or mixtures of hydrophobic agents that form anocclusive film on skin that reduces transepidermal water loss (TEWL) bypreventing evaporation of water from the stratum corneum.

As used herein, the term “stiffening agent component” refers to asubstance or mixture of substances that increases the viscosity and/orconsistency of the cream or improves the rheology of the cream.

As used herein, the term “emollient component” refers to an agent thatsoftens or soothes the skin or soothes an irritated internal surface.

As used herein, the term “stabilizing agent component” refers to asubstance or mixture of substances that improves the stability of thecream and/or the compatibility of the components in the cram. In someembodiments, the stabilizing agent component prevents agglomeration ofthe emulsion and stabilizes the droplets in the oil-in-water emulsion.

As used herein, the term “solvent component” is a liquid substance ormixture of liquid substances capable of dissolving ruxolitinib (or itssalt) or other substances in the cream. In some embodiments, the solventcomponent is a liquid substance or mixture of liquid substances in whichruxolitinib, or its pharmaceutically acceptable salt, has reasonablesolubility. For example, solubilities of ruxolitinib (free base) or itsphosphate salt (1:1 salt) are reported in Table 1. In some embodiments,a solvent is a substance or mixture thereof, in which ruxolitinib, orits pharmaceutically acceptable salt (whichever is used), has asolubility of at least about 10 mg/mL or greater, at least about 15mg/mL or greater, or at least about 20 mg/mL or greater, when measuredas described in Example 2.

As used herein, the phrase “antimicrobial preservative component” is asubstance or mixtures of substances which inhibits microbial growth inthe cream.

As used herein, the phrase “chelating agent component” refers to acompound or mixtures of compounds that has the ability to bind stronglywith metal ions.

As used herein, “% by weight of the emulsion” means the percentconcentration of the component in the emulsion is on weight/weightbasis. For example, 1% w/w of component A=[(mass of component A)/(totalmass of the emulsion)]×100.

As used herein, “% by weight of the emulsion on a free base basis” ofruxolitinib, or pharmaceutically acceptable salt thereof” means that the% w/w is calculated based on the weight of ruxolitinib in the totalemulsion. For example, “1.5% w/w on a free base basis” of ruxolitinibphosphate means that for 100 grams of total formulation, there are 1.98grams of ruxolitinib phosphate in the emulsion (which equates to 1.5grams of the free base, ruxolitinib).

As used herein, the term “component” can mean one substance or a mixtureof substances.

As used herein, the term “fatty acid” refers to an aliphatic acid thatis saturated or unsaturated. In some embodiments, the fatty acid is in amixture of different fatty acids. In some embodiments, the fatty acidhas between about eight to about thirty carbons on average. In someembodiments, the fatty acid has about 12 to 20, 14-20, or 16-18 carbonson average. Suitable fatty acids include, but are not limited to, cetylacid, stearic acid, lauric acid, myristic acid, erucic acid, palmiticacid, palmitoleic acid, capric acid, caprylic acid, oleic acid, linoleicacid, linolenic acid, hydroxystearic acid, 12-hydroxystearic acid,cetostearic acid, isostearic acid, sesquioleic acid,sesqui-9-octadecanoic acid, sesquiisooctadecanoic acid, behenic acid,isobehenic acid, and arachidonic acid, or mixtures thereof.

As used herein, the term “fatty alcohol” refers to an aliphatic alcoholthat is saturated or unsaturated. In some embodiments, the fatty alcoholis in a mixture of different fatty alcohols. In some embodiments, thefatty alcohol has between about 12 to about 20, about 14 to about 20, orabout 16 to about 18 carbons on average. Suitable fatty alcoholsinclude, but are not limited to, stearyl alcohol, lauryl alcohol,palmityl alcohol, cetyl alcohol, capryl alcohol, caprylyl alcohol, oleylalcohol, linolenyl alcohol, arachidonic alcohol, behenyl alcohol,isobehenyl alcohol, selachyl alcohol, chimyl alcohol, and linoleylalcohol, or mixtures thereof.

As used herein, the term “polyalkylene glycol”, employed alone or incombination with other terms, refers to a polymer containing oxyalkylenemonomer units, or copolymer of different oxyalkylene monomer units,wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms.As used herein, the term “oxyalkylene”, employed alone or in combinationwith other terms, refers to a group of formula —O-alkylene-. In someembodiments, the polyalkylene glycol is polyethylene glycol.

As used herein, the term, “sorbitan fatty ester” includes productsderived from sorbitan or sorbitol and fatty acids and, optionally,poly(ethylene glycol) units, including sorbitan esters andpolyethoxylated sorbitan esters. In some embodiments, the sorbitan fattyester is a polyethoxylated sorbitan ester.

As used herein, the term “sorbitan ester” refers to a compound, ormixture of compounds, derived from the esterification of sorbitol and atleast one fatty acid. Fatty acids useful for deriving the sorbitanesters include, but are not limited to, those described herein. Suitablesorbitan esters include, but are not limited to, the Span™ series(available from Uniqema), which includes Span 20 (sorbitan monolaurate),40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 65 (sorbitantristearate), 80 (sorbitan monooleate), and 85 (sorbitan trioleate).Other suitable sorbitan esters include those listed in R. C. Rowe and P.J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., whichis incorporated herein by reference in its entirety.

As used herein, the term “polyethoxylated sorbitan ester” refers to acompound, or mixture thereof, derived from the ethoxylation of asorbitan ester. The polyoxethylene portion of the compound can bebetween the fatty ester and the sorbitan moiety. As used herein, theterm “sorbitan ester” refers to a compound, or mixture of compounds,derived from the esterification of sorbitol and at least one fatty acid.Fatty acids useful for deriving the polyethoyxlated sorbitan estersinclude, but are not limited to, those described herein. In someembodiments, the polyoxyethylene portion of the compound or mixture hasabout 2 to about 200 oxyethylene units. In some embodiments, thepolyoxyethylene portion of the compound or mixture has about 2 to about100 oxyethylene units. In some embodiments, the polyoxyethylene portionof the compound or mixture has about 4 to about 80 oxyethylene units. Insome embodiments, the polyoxyethylene portion of the compound or mixturehas about 4 to about 40 oxyethylene units. In some embodiments, thepolyoxyethylene portion of the compound or mixture has about 4 to about20 oxyethylene units. Suitable polyethoxylated sorbitan esters include,but are not limited to the Tween™ series (available from Uniqema), whichincludes Tween 20 (POE(20) sorbitan monolaurate), 21 (POE(4) sorbitanmonolaurate), 40 (POE(20) sorbitan monopalmitate), 60 (POE(20) sorbitanmonostearate), 60K (POE(20) sorbitan monostearate), 61 (POE(4) sorbitanmonostearate), 65 (POE(20) sorbitan tristearate), 80 (POE(20) sorbitanmonooleate), 80K (POE(20) sorbitan monooleate), 81 (POE(5) sorbitanmonooleate), and 85 (POE(20) sorbitan trioleate). As used herein, theabbreviation “POE” refers to polyoxyethylene. The number following thePOE abbreviation refers to the number of oxyethylene repeat units in thecompound. Other suitable polyethoxylated sorbitan esters include thepolyoxyethylene sorbitan fatty acid esters listed in R. C. Rowe and P.J. Shesky, Handbook of pharmaceutical excipients, (2006), 5th ed., whichis incorporated herein by reference in its entirety. In someembodiments, the polyethoxylated sorbitan ester is a polysorbate. Insome embodiments, the polyethoxylated sorbitan ester is polysorbate 20.

As used herein, the term “glyceryl fatty esters” refers to mono-, di- ortriglycerides of fatty acids. The glyceryl fatty esters may beoptionally substituted with sulfonic acid groups, or pharmaceuticallyacceptable salts thereof. Suitable fatty acids for deriving glyceridesof fatty acids include, but are not limited to, those described herein.In some embodiments, the glyceryl fatty ester is a mono-glyceride of afatty acid having 12 to 18 carbon atoms. In some embodiments, theglyceryl fatty ester is glyceryl stearate.

As used herein, the term “triglycerides” refers to a triglyceride of afatty acid. In some embodiments, the triglyceride is medium chaintriglycerides.

As used herein, the term “alkylene glycol” refers to a group of formula—O-alkylene-, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3carbon atoms. In some embodiments, the alkylene glycol is propyleneglycol (1,2-propanediol).

As used herein, the term “polyethylene glycol” refers to a polymercontaining ethylene glycol monomer units of formula —O—CH₂—CH₂—.Suitable polyethylene glycols may have a free hydroxyl group at each endof the polymer molecule, or may have one or more hydroxyl groupsetherified with a lower alkyl, e.g., a methyl group. Also suitable arederivatives of polyethylene glycols having esterifiable carboxy groups.Polyethylene glycols useful in the present disclosure can be polymers ofany chain length or molecular weight, and can include branching. In someembodiments, the average molecular weight of the polyethylene glycol isfrom about 200 to about 9000. In some embodiments, the average molecularweight of the polyethylene glycol is from about 200 to about 5000. Insome embodiments, the average molecular weight of the polyethyleneglycol is from about 200 to about 900. In some embodiments, the averagemolecular weight of the polyethylene glycol is about 400. Suitablepolyethylene glycols include, but are not limited to polyethyleneglycol-200, polyethylene glycol-300, polyethylene glycol-400,polyethylene glycol-600, and polyethylene glycol-900. The numberfollowing the dash in the name refers to the average molecular weight ofthe polymer.

In some embodiments, “about” means plus or minus 10% of the value.

Cream Formulations

In some embodiments, the cream formulation is an oil-in-water emulsion.In some embodiments, the cream is a solubilized cream. In someembodiments, the cream has a pH from about 2.8 to about 3.6. In thecontext of pH, “about” refers to ±0.3 (preferably ±0.2 or morepreferably ±0.1).

In some embodiments, the cream comprises an oil-in-water emulsion,comprising 1.5% (w/w) on a free base basis of ruxolitinib phosphate.

In some embodiments, the cream is an oil-in-water emulsion as describedin US 2015/0250790, which is incorporated herein by reference in itsentirety. In particular, Examples 3-6 of US 2015/0250790 (andparticularly Tables 3-5 and accompanying text) are incorporated hereinby reference.

In some embodiments, the oil component is present in an amount of about10% to about 40% by weight of the emulsion.

In some embodiments, the oil component is present in an amount of about10% to about 24% by weight of the emulsion.

In some embodiments, the oil component is present in an amount of about15% to about 24% by weight of the emulsion.

In some embodiments, the oil component is present in an amount of about18% to about 24% by weight of the emulsion.

In some embodiments, the oil component comprises one or more substancesindependently selected from petrolatums, fatty alcohols, mineral oils,triglycerides, and silicone oils.

In some embodiments, the oil component comprises one or more substancesindependently selected from white petrolatum, cetyl alcohol, stearylalcohol, light mineral oil, medium chain triglycerides, and dimethicone.

In some embodiments, the oil component comprises an occlusive agentcomponent.

In some embodiments, the occlusive agent component is present in anamount of about 2% to about 15% by weight of the emulsion.

In some embodiments, the occlusive agent component is present in anamount of about 5% to about 10% by weight of the emulsion.

In some embodiments, the occlusive agent component comprises one or moresubstances selected from fatty acids (e.g., lanolin acid), fattyalcohols (e.g., lanolin alcohol), hydrocarbon oils & waxes (e.g.,petrolatum), polyhydric alcohols (e.g., propylene glycol), silicones(e.g., dimethicone), sterols (e.g., cholesterol), vegetable or animalfat (e.g., cocoa butter), vegetable wax (e.g., Carnauba wax), and waxester (e.g., bees wax).

In some embodiments, the occlusive agent component comprises one or moresubstances selected from lanolin acid fatty alcohols, lanolin alcohol,petrolatum, propylene glycol, dimethicone, cholesterol, cocoa butter,Carnauba wax, and bees wax.

In some embodiments, the occlusive agent component comprises petrolatum.

In some embodiments, the occlusive agent component comprises whitepetrolatum.

In some embodiments, the oil component comprises a stiffening agentcomponent.

In some embodiments, the stiffening agent component is present in anamount of about 2% to about 8% by weight of the emulsion.

In some embodiments, the stiffening agent component is present in anamount of about 3% to about 6% by weight of the emulsion.

In some embodiments, the stiffening agent component is present in anamount of about 4% to about 7% by weight of the emulsion.

In some embodiments, the stiffening agent component comprises one ormore substances independently selected from fatty alcohols.

In some embodiments, the stiffening agent component comprises one ormore substances independently selected from C₁₂₋₂₀ fatty alcohols.

In some embodiments, the stiffening agent component comprises one ormore substances independently selected from C₁₆₋₁₈ fatty alcohols.

In some embodiments, the stiffening agent component comprises one ormore substances independently selected from cetyl alcohol and stearylalcohol.

In some embodiments, the oil component comprises an emollient component.

In some embodiments, the emollient component is present in an amount ofabout 5% to about 15% by weight of the emulsion.

In some embodiments, the emollient component is present in an amount ofabout 7% to about 13% by weight of the emulsion.

In some embodiments, the emollient component comprises one or moresubstances independently selected from mineral oils and triglycerides.

In some embodiments, the emollient component comprises one or moresubstances independently selected from light mineral oil and mediumchain triglycerides.

In some embodiments, the emollient component comprises one or moresubstances independently selected from light mineral oil, medium chaintriglycerides, and dimethicone.

In some embodiments, the water is present in an amount of about 35% toabout 65% by weight of the emulsion.

In some embodiments, the water is present in an amount of about 40% toabout 60% by weight of the emulsion.

In some embodiments, the water is present in an amount of about 45% toabout 55% by weight of the emulsion.

In some embodiments, the emulsifier component is present in an amount ofabout 1% to about 9% by weight of the emulsion.

In some embodiments, the emulsifier component is present in an amount ofabout 2% to about 6% by weight of the emulsion.

In some embodiments, the emulsifier component is present in an amount ofabout 3% to about 5% by weight of the emulsion.

In some embodiments, the emulsifier component is present in an amount ofabout 4% to about 7% by weight of the emulsion.

In some embodiments, the emulsion comprises an emulsifier component anda stiffening agent component, wherein the combined amount of emulsifiercomponent and stiffening agent component is at least about 8% by weightof the emulsion.

In some embodiments, the emulsifier component comprises one or moresubstances independently selected from glyceryl fatty esters andsorbitan fatty esters.

In some embodiments, the emulsifier component comprises one or moresubstances independently selected from glyceryl stearate, andpolysorbate 20.

In some embodiments, the emulsion further comprises a stabilizing agentcomponent.

In some embodiments, the stabilizing agent component is present in anamount of about 0.05% to about 5% by weight of the emulsion.

In some embodiments, the stabilizing agent component is present in anamount of about 0.1% to about 2% by weight of the emulsion.

In some embodiments, the stabilizing agent component is present in anamount of about 0.3% to about 0.5% by weight of the emulsion.

In some embodiments, the stabilizing agent component comprises one ormore substances independently selected from polysaccharides.

In some embodiments, the stabilizing agent component comprises xanthangum.

In some embodiments, the emulsion further comprises a solvent component.

In some embodiments, the solvent component is present in an amount ofabout 10% to about 35% by weight of the emulsion.

In some embodiments, the solvent component is present in an amount ofabout 15% to about 30% by weight of the emulsion.

In some embodiments, the solvent component is present in an amount ofabout 20% to about 25% by weight of the emulsion.

In some embodiments, the solvent component comprises one or moresubstances independently selected from alkylene glycols and polyalkyleneglycols.

In some embodiments, the solvent component comprises one or moresubstances independently selected from propylene glycol and polyethyleneglycol.

In some embodiments, the emulsion comprises:

-   -   from about 35% to about 65% of water by weight of the emulsion;    -   from about 10% to about 40% of an oil component by weight of the        emulsion;    -   from about 1% to about 9% of an emulsifier component by weight        of the emulsion;    -   from about 10% to about 35% of a solvent component by weight of        the emulsion;    -   from about 0.05% to about 5% of a stabilizing agent component by        weight of the emulsion; and    -   from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically        acceptable salt thereof, by weight of the emulsion on a free        base basis.

In some embodiments, the emulsion comprises:

-   -   from about 35% to about 65% of water by weight of the emulsion;    -   from about 10% to about 24% of an oil component by weight of the        emulsion;    -   from about 1% to about 9% of an emulsifier component by weight        of the emulsion;    -   from about 10% to about 35% of a solvent component by weight of        the emulsion;    -   from about 0.05% to about 5% of a stabilizing agent component by        weight of the emulsion; and    -   from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically        acceptable salt thereof, by weight of the emulsion on a free        base basis.

In some embodiments, the emulsion comprises:

-   -   from about 40% to about 60% of water by weight of the emulsion;    -   from about 15% to about 30% of an oil component by weight of the        emulsion;    -   from about 2% to about 6% of an emulsifier component by weight        of the emulsion;    -   from about 15% to about 30% of a solvent component by weight of        the emulsion;    -   from about 0.1% to about 2% of a stabilizing agent component by        weight of the emulsion; and    -   from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically        acceptable salt thereof, by weight of the emulsion on a free        base basis.

In some embodiments, the emulsion comprises:

-   -   from about 40% to about 60% of water by weight of the emulsion;    -   from about 15% to about 30% of an oil component by weight of the        emulsion;    -   from about 2% to about 6% of an emulsifier component by weight        of the emulsion;    -   from about 15% to about 24% of a solvent component by weight of        the emulsion;    -   from about 0.1% to about 2% of a stabilizing agent component by        weight of the emulsion; and    -   from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically        acceptable salt thereof, by weight of the emulsion on a free        base basis.

In some embodiments, the emulsion comprises:

-   -   from about 45% to about 55% of water by weight of the emulsion;    -   from about 15% to about 24% of an oil component by weight of the        emulsion;    -   from about 3% to about 5% of an emulsifier component by weight        of the emulsion;    -   from about 20% to about 25% of a solvent component by weight of        the emulsion;    -   from about 0.3% to about 0.5% of a stabilizing agent component        by weight of the emulsion; and    -   from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically        acceptable salt thereof, by weight of the emulsion on a free        base basis.

In some embodiments, the emulsion comprises:

-   -   from about 45% to about 55% of water by weight of the emulsion;    -   from about 15% to about 24% of an oil component by weight of the        emulsion;    -   from about 4% to about 7% of an emulsifier component by weight        of the emulsion;    -   from about 20% to about 25% of a solvent component by weight of        the emulsion;    -   from about 0.3% to about 0.5% of a stabilizing agent component        by weight of the emulsion; and    -   from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically        acceptable salt thereof, by weight of the emulsion on a free        base basis.

In some embodiments:

-   -   the oil component comprises one or more substances independently        selected from petrolatums, fatty alcohols, mineral oils,        triglycerides, and dimethicones;    -   the emulsifier component comprises one or more substances        independently selected from glyceryl fatty esters and sorbitan        fatty esters;    -   the solvent component comprises one or more substances        independently selected from alkylene glycols and polyalkylene        glycols; and    -   the stabilizing agent component comprises one or more substances        independently selected from polysaccharides.

In some embodiments:

-   -   the oil component comprises one or more substances independently        selected from white petrolatum, cetyl alcohol, stearyl alcohol,        light mineral oil, medium chain triglycerides, and dimethicone;    -   the emulsifier component comprises one or more substances        independently selected from glyceryl stearate and polysorbate        20;    -   the solvent component comprises one or more substances        independently selected from propylene glycol and polyethylene        glycol; and    -   the stabilizing agent component comprises xanthan gum.

In some embodiments, the emulsion comprises:

-   -   from about 35% to about 65% of water by weight of the emulsion;    -   from about 2% to about 15% of an occlusive agent component by        weight of the emulsion;    -   from about 2% to about 8% of a stiffening agent component by        weight of the emulsion;    -   from about 5% to about 15% of an emollient component by weight        of the emulsion;    -   from about 1% to about 9% of an emulsifier component by weight        of the emulsion;    -   from about 0.05% to about 5% of a stabilizing agent component by        weight of the emulsion;    -   from about 10% to about 35% of a solvent component by weight of        the emulsion;    -   and from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically        acceptable salt thereof, by weight of the emulsion on a free        base basis.

In some embodiments, the emulsion comprises:

-   -   from about 40% to about 60% of water by weight of the emulsion;    -   from about 5% to about 10% of an occlusive agent component by        weight of the emulsion;    -   from about 2% to about 8% of a stiffening agent component by        weight of the emulsion;    -   from about 7% to about 12% of an emollient component by weight        of the emulsion;    -   from about 2% to about 6% of an emulsifier component by weight        of the emulsion;    -   from about 0.1% to about 2% of a stabilizing agent by weight of        the emulsion;    -   from about 15% to about 30% of a solvent component by weight of        the emulsion;    -   and from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically        acceptable salt thereof, by weight of the emulsion on a free        base basis.

In some embodiments, the emulsion comprises:

-   -   from about 45% to about 55% of water by weight of the emulsion;    -   from about 5% to about 10% of an occlusive agent component by        weight of the emulsion;    -   from about 3% to about 6% of a stiffening agent component by        weight of the emulsion;    -   from about 7% to about 13% of an emollient component by weight        of the emulsion;    -   from about 3% to about 5% of an emulsifier component by weight        of the emulsion;    -   from about 0.3% to about 0.5% of a stabilizing agent component        by weight of the emulsion;    -   from about 20% to about 25% of a solvent component by weight of        the emulsion;    -   and from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically        acceptable salt thereof, by weight of the emulsion on a free        base basis.

In some embodiments, the emulsion comprises:

-   -   from about 45% to about 55% of water by weight of the emulsion;    -   from about 5% to about 10% of an occlusive agent component by        weight of the emulsion;    -   from about 4% to about 7% of a stiffening agent component by        weight of the emulsion;    -   from about 7% to about 13% of an emollient component by weight        of the emulsion;    -   from about 4% to about 7% of an emulsifier component by weight        of the emulsion;    -   from about 0.3% to about 0.5% of a stabilizing agent component        by weight of the emulsion;    -   from about 20% to about 25% of a solvent component by weight of        the emulsion;    -   and from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically        acceptable salt thereof, by weight of the emulsion on a free        base basis.

In some embodiments, the emulsion comprises:

-   -   from about 45% to about 55% of water by weight of the emulsion;    -   about 7% of an occlusive agent component by weight of the        emulsion;    -   from about 4.5% to about 5% of a stiffening agent component by        weight of the emulsion;    -   about 10% of an emollient component by weight of the emulsion;    -   from about 4% to about 4.5% of an emulsifier component by weight        of the emulsion;    -   about 0.4% of a stabilizing agent component by weight of the        emulsion;    -   about 22% of a solvent component by weight of the emulsion; and    -   from 0.5% to 1.5% of ruxolitinib, or a pharmaceutically        acceptable salt thereof, by weight of the emulsion on a free        base basis.

In some embodiments, the ruxolitinib, or pharmaceutically acceptablesalt thereof, is present as ruxolitinib phosphate.

In some embodiments, the emulsion comprises 1.5% of ruxolitinib, or apharmaceutically acceptable salt thereof, by weight of the emulsion.

In some embodiments, the emulsion comprises 1.5% of ruxolitinibphosphate by weight of the emulsion.

In some embodiments, the emulsion comprises 0.75% of ruxolitinib, or apharmaceutically acceptable salt thereof, by weight of the emulsion.

In some embodiments, the emulsion comprises 0.75% of ruxolitinibphosphate by weight of the emulsion.

In some embodiments, the combined amount of the stiffening agentcomponent and the emulsifier component is at least about 8% by weight ofthe emulsion.

In some embodiments:

-   -   the occlusive agent component comprises a petrolatum;    -   the stiffening agent component comprises one or more substances        independently selected from one or more fatty alcohols;    -   the emollient component comprises one or more substances        independently selected from mineral oils and triglycerides;    -   the emulsifier component comprises one or more substances        independently selected from glyceryl fatty esters and sorbitan        fatty esters;    -   the stabilizing agent component comprises one or more substances        independently selected from polysaccharides; and    -   the solvent component comprises one or more substances        independently selected from alkylene glycols and polyalkylene        glycols.

In some embodiments:

-   -   the occlusive agent component comprises white petrolatum;    -   the stiffening agent component comprises one or more substances        independently selected from cetyl alcohol and stearyl alcohol;    -   the emollient component comprises one or more substances        independently selected from light mineral oil, medium chain        triglycerides, and dimethicone;    -   the emulsifier component comprises one or more substances        independently selected from glyceryl stearate and polysorbate        20;    -   the stabilizing agent component comprises xanthan gum; and    -   the solvent component comprises one or more substances        independently selected from propylene glycol and polyethylene        glycol.

In some embodiments, the emulsion further comprises an antimicrobialpreservative component.

In some embodiments, the antimicrobial preservative component is presentin an amount of about 0.05% to about 3% by weight of the emulsion.

In some embodiments, the antimicrobial preservative component is presentin an amount of about 0.1% to about 1% by weight of the emulsion.

In some embodiments, the antimicrobial preservative component comprisesone or more substances independently selected from alkyl parabens andphenoxyethanol.

In some embodiments, the antimicrobial preservative component comprisesone or more substances independently selected from methyl paraben,propyl paraben, and phenoxyethanol.

In some embodiments, the emulsion further comprises a chelating agentcomponent.

In some embodiments, the chelating agent component comprises edetatedisodium.

Ruxolitinib can be prepared as described in U.S. Pat. No. 7,598,257 andU.S. Patent Publ. No. 2009/0181959, each of which is incorporated hereinby reference in its entirety. The 1:1 phosphate salt of ruxolitinib canbe prepared as described in U.S. Patent Publ. No. 2008/0312259, which isincorporated herein by reference in its entirety.

As will be appreciated, some components of the cream (emulsion)described herein can possess multiple functions. For example, a givensubstance may act as both an emulsifying agent component and astabilizing agent. In some such cases, the function of a given componentcan be considered singular, even though its properties may allowmultiple functionality. In some embodiments, each component of theformulation comprises a different substance or mixture of substances.

It is further appreciated that certain features of the disclosure, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the disclosure which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

The following embodiments are provided:

-   -   1. A method of reducing itch in a human patient with atopic        dermatitis, comprising administering to the skin of said human        patient in need thereof, a cream formulation two times per day,        wherein said cream formulation comprises 1.5% (w/w) on a free        base basis of ruxolitinib phosphate,        -   wherein said patient achieves a reduction in the itch            Numerical Rating Scale score from baseline.    -   2. The method of embodiment 1, wherein said patient:        -   is aged 18 to 70 years,        -   has been diagnosed with atopic dermatitis for at least 2            years,        -   has an IGA score of 2 to 3 at screening and baseline, and        -   has a BSA of atopic dermatitis involvement (excluding face            and intertriginous areas) of 3% to 20% at baseline.    -   3. The method of embodiment 1 or 2, wherein the patient is        diagnosed with atopic dermatitis as defined by the Hanifin and        Rajika criteria.    -   4. The method of any one of embodiments 1-3, wherein said the        two administrations per day are at least 8 hours apart.    -   5. The method of any one of embodiments 1-4, wherein the cream        formulation is an oil-in-water emulsion comprising said 1.5%        (w/w) on a free base basis of ruxolitinib phosphate.    -   6. The method of any one of embodiments 1-5, wherein the cream        formulation has a pH from about 2.8 to about 3.6.    -   7. The method of any one of embodiments 1-6, wherein the cream        formulation is a solubilized cream.    -   8. The method of any one of embodiments 1-7, wherein the patient        achieves a statistically significant reduction in itch Numerical        Rating Scale score from baseline at day 2 of said administering        compared to a patient administered placebo for the same period.    -   9. The method of any one of embodiments 1-8, wherein the patient        achieves at least a 1.5 point reduction in itch Numerical Rating        Scale score from baseline at day 2 of said administering.    -   10. The method of any one of embodiments 1-9, wherein the        patient achieves a statistically significant reduction in itch        Numerical Rating Scale score from baseline at week 2 of said        administering compared to a patient administered placebo for the        same period.    -   11. The method of any one of embodiments 1-10, wherein the        patient achieves at least a 3 point reduction in itch Numerical        Rating Scale score from baseline at week 2 of said        administering.    -   12. The method of any one of embodiments 1-11, wherein the        patient achieves a statistically significant reduction in itch        Numerical Rating Scale score from baseline at week 4 of said        administering compared to a patient administered placebo for the        same period.    -   13. The method of any one of embodiments 1-12, wherein the        patient achieves at least a 3 point reduction in itch Numerical        Rating Scale score from baseline at week 4 of said        administering.    -   14. The method of any one of embodiments 1-13, wherein the        patient achieves a statistically significant reduction in itch        Numerical Rating Scale score from baseline at week 8 of said        administering compared to a patient administered placebo for the        same period.    -   15. The method of any one of embodiments 1-14, wherein the        patient achieves at least a 3 point reduction in itch Numerical        Rating Scale score from baseline at week 8 of said        administering.    -   16. The method of any one of embodiments 1-15, wherein the        patient achieves at least a 4 point reduction in itch Numerical        Rating Scale score from baseline at week 8 of said        administering.    -   17. The method of any one of embodiments 1-16, wherein the        patient achieves at least a 4.5 point reduction in itch        Numerical Rating Scale score from baseline at week 12 of said        administering.    -   18. The method of any one of embodiments 1-17, wherein said        administering reverses the symptomatology of atopic dermatitis.    -   19. The method of any one of embodiments 1-18, wherein the        patient achieves a statistically significant improvement in        Eczema Area and Severity Index score from baseline at week 4 of        said administering compared to a patient administered placebo        for the same period.    -   20. The method of any one of embodiments 1-19, wherein the        patient achieves a statistically significant improvement in        Eczema Area and Severity Index score from baseline at week 8 of        said administering compared to a patient administered placebo        for the same period.    -   21. The method of any one of embodiments 1-20, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 2 of said administering.    -   22. The method of any one of embodiments 1-21, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 4 of said administering.    -   23. The method of any one of embodiments 1-22, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 8 of said administering.    -   24. The method of any one of embodiments 1-23, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 12 of said administering.    -   25. The method of any one of embodiments 1-24, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 2        weeks of said administering.    -   26. The method of any one of embodiments 1-25, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 4        weeks of said administering.    -   27. The method of any one of embodiments 1-26, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 8        weeks of said administering.    -   28. The method of any one of embodiments 1-27, wherein the        patient achieves a clinically meaningful improvement in the        PROMIS Short Form—Sleep Disturbances (8b) 24-hour recall score        at Week 8.    -   29. The method of any one of embodiments 1-28, wherein said        administering is maintained for at least 2 weeks.    -   30. The method of any one of embodiments 1-29, wherein said        administering is maintained for at least 4 weeks.    -   31. The method of any one of embodiments 1-30, wherein said        administering is maintained for at least 8 weeks.    -   32. The method of any one of embodiments 1-31, wherein said        administering is maintained for at least 12 weeks.    -   33. The method of any one of embodiments 1-32, wherein the        patient did not use topical treatments for atopic dermatitis,        other than bland emollients, within 2 weeks of baseline; and did        not use systemic immunosuppressive or systemic immunomodulating        drugs within 4 weeks of baseline.    -   34. The method of any one of embodiments 1-33, wherein the        patient is not administered other therapeutic agents used to        treat atopic dermatitis.    -   35. A method of reducing itch in a human patient with atopic        dermatitis, comprising administering to the skin of said human        patient in need thereof, a cream formulation two times per day,        wherein said cream formulation is an oil-in-water emulsion,        comprising 1.5% (w/w) on a free base basis of ruxolitinib        phosphate,        -   wherein said administering is maintained for at least 8            weeks,        -   wherein the patient achieves at least a 4 point reduction in            itch NRS score from baseline at week 8 of said            administering, and        -   wherein the patient achieves an Investigator's Global            Assessment score of 0 or 1 with an improvement of at least 2            points from baseline at 8 weeks of said administering.    -   36. The method of embodiment 35, wherein the patient achieves an        Investigator's Global Assessment score of 0 or 1 with an        improvement of at least 2 points from baseline at 8 weeks of        said administering.    -   37. The method of embodiment 35 or 36, wherein the patient is:        -   is aged 18 to 70 years,        -   has been diagnosed with atopic dermatitis for at least 2            years,        -   has an IGA score of 2 to 3 at screening and baseline, and        -   has a BSA of atopic dermatitis involvement (excluding face            and intertriginous areas) of 3% to 20% at baseline.    -   38. A method of reducing itch in a human patient with atopic        dermatitis, comprising administering to the skin of said human        patient in need thereof, a cream formulation two times per day,        wherein said cream formulation comprises 1.5% (w/w) on a free        base basis of ruxolitinib, or a pharmaceutically acceptable salt        thereof,        -   wherein said patient achieves a reduction in the itch            Numerical Rating Scale score from baseline.    -   39. A method of reducing itch in a human patient with atopic        dermatitis, comprising administering to the skin of said human        patient in need thereof, a cream formulation two times per day,        wherein said cream formulation comprises 0.75% (w/w) on a free        base basis of ruxolitinib, or a pharmaceutically acceptable salt        thereof,        -   wherein said patient achieves a reduction in the itch            Numerical Rating Scale score from baseline.    -   40. The method of embodiment 38 or 39, wherein the ruxolitinib,        or a pharmaceutically acceptable salt thereof, is ruxolitinib        phosphate.    -   41. The method of any one of embodiments 38-40, wherein said        patient:        -   is aged 18 to 70 years,        -   has been diagnosed with atopic dermatitis for at least 2            years,        -   has an Investigator's Global Assessment score of 2 to 3 at            screening and baseline, and        -   has a BSA of atopic dermatitis involvement (excluding face            and intertriginous areas) of 3% to 20% at baseline.    -   42. The method of any one of embodiments 38-41, wherein the        patient is diagnosed with atopic dermatitis as defined by the        Hanifin and Rajika criteria.    -   43. The method of any one of embodiments 38-42, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline.    -   44. The method of any one of embodiments 38-43, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline, wherein the        patient has a baseline Numerical Rating Scale score of equal to        or greater than 4.    -   45. The method of any one of embodiments 38-44, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline after 2 weeks        of said administering, wherein the patient has a baseline        Numerical Rating Scale score of equal to or greater than 4.    -   46. The method of any one of embodiments 38-45, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline after 4 weeks        of said administering, wherein the patient has a baseline        Numerical Rating Scale score of equal to or greater than 4.    -   47. The method of any one of embodiments 38-46, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline after 8 weeks        of said administering, wherein the patient has a baseline        Numerical Rating Scale score of equal to or greater than 4.    -   48. The method of any one of embodiments 38-47, wherein the        patient achieves at least a 2 point improvement in itch        Numerical Rating Scale score from baseline at day 2 of said        administering.    -   49. The method of any one of embodiments 38-49, wherein the        patient achieves a prompt reduction of itch.    -   50. The method of any one of embodiments 38-49, wherein the        patient achieves a statistically significant reduction of itch        at day 1 of said administering.    -   51. The method of any one of embodiments 38-50, wherein the        patient achieves a statistically significant reduction in itch        Numerical Rating Scale score from baseline at day 1 of said        administering compared to a patient administered placebo for the        same period.    -   52. The method of any one of embodiments 38-51, wherein the        patient achieves at least a 1 point reduction in itch Numerical        Rating Scale score from baseline at day 1 of said administering.    -   53. The method of any one of embodiments 38-52, wherein the        patient achieves a statistically significant reduction in itch        Numerical Rating Scale score from baseline at day 2 of said        administering compared to a patient administered placebo for the        same period.    -   54. The method of any one of embodiments 38-53, wherein the        patient achieves at least a 2 point reduction in itch Numerical        Rating Scale score from baseline at day 2 of said administering.    -   55. The method of any one of embodiments 38-54, wherein the        patient achieves at least a 3 point reduction in itch Numerical        Rating Scale score from baseline at week 2 of said        administering.    -   56. The method of any one of embodiments 38-55, wherein the        patient achieves at least a 3 point reduction in itch Numerical        Rating Scale score from baseline at week 4 of said        administering.    -   57. The method of any one of embodiments 38-56, wherein the        patient achieves at least a 3 point reduction in itch Numerical        Rating Scale score from baseline at week 8 of said        administering.    -   58. The method of any one of embodiments 38-57, wherein the        patient achieves at least a 4 point reduction in itch Numerical        Rating Scale score from baseline at week 2 of said        administering.    -   59. The method of any one of embodiments 38-58, wherein the        patient achieves at least a 4 point reduction in itch Numerical        Rating Scale score from baseline at week 4 of said        administering.    -   60. The method of any one of embodiments 38-59, wherein the        patient achieves at least a 4 point reduction in itch Numerical        Rating Scale score from baseline at week 8 of said        administering.    -   61. The method of any one of embodiments 38-60, wherein said        administering reverses the symptomatology of atopic dermatitis.    -   62. The method of any one of embodiments 38-61, wherein the        patient achieves a statistically significant improvement in        Eczema Area and Severity Index score from baseline at week 4 of        said administering compared to a patient administered placebo        for the same period.    -   63. The method of any one of embodiments 38-62, wherein the        patient achieves a statistically significant improvement in        Eczema Area and Severity Index score from baseline at week 8 of        said administering compared to a patient administered placebo        for the same period.    -   64. The method of any one of embodiments 38-63, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 2 of said administering.    -   65. The method of any one of embodiments 38-64, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 4 of said administering.    -   66. The method of any one of embodiments 38-65, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 8 of said administering.    -   67. The method of any one of embodiments 38-66, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 12 of said administering.    -   68. The method of any one of embodiments 38-67, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 2        weeks of said administering.    -   69. The method of any one of embodiments 38-68, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 4        weeks of said administering.    -   70. The method of any one of embodiments 38-69, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 8        weeks of said administering.    -   71. The method of any one of embodiments 38-70, wherein the        patient achieves a clinically meaningful improvement in the        PROMIS Short Form—Sleep Disturbances (8b) 24-hour recall score        at Week 8.    -   72. The method of any one of embodiments 38-71, wherein said        administering is maintained for at least 2 weeks.    -   73. The method of any one of embodiments 38-72, wherein said        administering is maintained for at least 4 weeks.    -   74. The method of any one of embodiments 38-73, wherein said        administering is maintained for at least 8 weeks.    -   75. The method of any one of embodiments 38-74, wherein said        administering is maintained for at least 12 weeks.    -   76. The method of any one of embodiments 38-75, wherein the        patient did not use topical treatments for atopic dermatitis,        other than bland emollients, within 2 weeks of baseline; and did        not use systemic immunosuppressive or systemic immunomodulating        drugs within 4 weeks of baseline.    -   77. The method of any one of embodiments 38-76, wherein the        patient is not administered other therapeutic agents used to        treat atopic dermatitis.    -   78. The method of any one of embodiments 38-77 wherein said        administering of said cream formulation does not result in a        statistically significant reduction in hemoglobin or platelets.    -   79. The method of any one of embodiments 38-78, wherein said        administering of said cream formulation does not result        administration site burn.    -   80. The method of any one of embodiments 38-79, wherein the        cream formulation is an oil-in-water emulsion comprising said        ruxolitinib, or pharmaceutically acceptable salt thereof.    -   81. The method of any one of embodiments 38-80, wherein the        cream formulation has a pH from about 2.8 to about 3.6.    -   82. The method of any one of embodiments 38-81, wherein the        cream formulation is a solubilized cream.    -   83. The method of any one of embodiments 38-82, wherein said the        two administrations per day are at least 8 hours apart.    -   84. A method of reducing itch in a human patient with atopic        dermatitis, comprising administering to the skin of said human        patient in need thereof, a cream formulation two times per day,        wherein said cream formulation is an oil-in-water emulsion,        comprising 1.5% (w/w) on a free base basis of ruxolitinib        phosphate,        -   wherein said administering is maintained for at least 8            weeks,        -   wherein the patient achieves at least a 4 point reduction in            itch NRS score from baseline at week 8 of said            administering, and        -   wherein the patient achieves an Investigator's Global            Assessment score of 0 or 1 with an improvement of at least 2            points from baseline at 8 weeks of said administering.    -   85. The method of embodiment 84, wherein the patient achieves an        Investigator's Global Assessment score of 0 or 1 with an        improvement of at least 2 points from baseline at 8 weeks of        said administering.    -   86. The method of embodiment 84 or 85, wherein the patient is:        -   is aged 18 to 70 years,        -   has been diagnosed with atopic dermatitis for at least 2            years,        -   has an Investigator's Global Assessment score of 2 to 3 at            screening and baseline, and        -   has a BSA of atopic dermatitis involvement (excluding face            and intertriginous areas) of 3% to 20% at baseline.    -   87. A method of treating atopic dermatitis in a human patient,        comprising administering to the skin of said human patient in        need thereof, a cream formulation two times per day, wherein        said cream formulation comprises 0.75% (w/w) on a free base        basis of ruxolitinib, or a pharmaceutically acceptable salt        thereof.    -   88. The method of embodiment 87, wherein the ruxolitinib, or a        pharmaceutically acceptable salt thereof, is ruxolitinib        phosphate.    -   89. The method of any one of embodiments 87-88, wherein the        patient achieves Investigator's Global Assessment score of 0 or        1 with an improvement of at least 2 points from baseline.    -   90. The method of any one of embodiments 87-89, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 2        weeks of said administering.    -   91. The method of any one of embodiments 87-90, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 4        weeks of said administering.    -   92. The method of any one of embodiments 87-91, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 8        weeks of said administering.    -   93. The method of any one of embodiments 87-92, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline.    -   94. The method of any one of embodiments 87-93, wherein the        patient achieves a statistically significant improvement in        Eczema Area and Severity Index score from baseline at week 4 of        said administering compared to a patient administered placebo        for the same period.    -   95. The method of any one of embodiments 87-94, wherein the        patient achieves a statistically significant improvement in        Eczema Area and Severity Index score from baseline at week 8 of        said administering compared to a patient administered placebo        for the same period.    -   96. The method of any one of embodiments 87-95, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 2 of said administering.    -   97. The method of any one of embodiments 87-96, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 4 of said administering.    -   98. The method of any one of embodiments 87-97, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 8 of said administering.    -   99. The method of any one of embodiments 87-98, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 12 of said administering.    -   100. The method of any one of embodiments 87-99, wherein the        patient achieves a clinically meaningful improvement in the        PROMIS Short Form—Sleep Disturbances (8b) 24-hour recall score.    -   101. The method of any one of embodiments 87-100, wherein the        patient achieves a clinically meaningful improvement in the        PROMIS Short Form—Sleep Disturbances (8b) 24-hour recall score        at Week 8.    -   102. The method of any one of embodiments 87-101, wherein said        administering is maintained for at least 2 weeks.    -   103. The method of any one of embodiments 87-102, wherein said        administering is maintained for at least 4 weeks.    -   104. The method of any one of embodiments 87-103, wherein said        administering is maintained for at least 8 weeks.    -   105. The method of any one of embodiments 87-104, wherein said        administering is maintained for at least 12 weeks.    -   106. The method of any one of embodiments 87-105, wherein the        patient did not use topical treatments for atopic dermatitis,        other than bland emollients, within 2 weeks of baseline; and did        not use systemic immunosuppressive or systemic immunomodulating        drugs within 4 weeks of baseline.    -   107. The method of any one of embodiments 87-106, wherein the        patient is not administered other therapeutic agents used to        treat atopic dermatitis.    -   108. The method of any one of embodiments 87-107, wherein said        the two administrations per day are at least 8 hours apart.    -   109. The method of any one of embodiments 87-108, wherein the        cream formulation is an oil-in-water emulsion comprising said        0.75% (w/w) on a free base basis of ruxolitinib phosphate.    -   110. The method of any one of embodiments 87-109, wherein the        cream formulation has a pH from about 2.8 to about 3.6.    -   111. The method of any one of embodiments 87-110, wherein the        cream formulation is a solubilized cream.    -   112. The method of any one of embodiments 87-111, wherein said        patient:        -   is aged 18 to 70 years,        -   has been diagnosed with atopic dermatitis for at least 2            years,        -   has an Investigator's Global Assessment score of 2 to 3 at            screening and baseline, and        -   has a BSA of atopic dermatitis involvement (excluding face            and intertriginous areas) of 3% to 20% at baseline.    -   113. The method of any one of embodiments 87-112, wherein the        patient is diagnosed with atopic dermatitis as defined by the        Hanifin and Rajika criteria.    -   114. The method of any one of embodiments 87-113, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline.    -   115. The method of any one of embodiments 87-114, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline, wherein the        patient has a baseline Numerical Rating Scale score of equal to        or greater than 4.    -   116. The method of any one of embodiments 87-115, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline after 2 weeks        of said administering, wherein the patient has a baseline        Numerical Rating Scale score of equal to or greater than 4.    -   117. The method of any one of embodiments 87-116, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline after 4 weeks        of said administering, wherein the patient has a baseline        Numerical Rating Scale score of equal to or greater than 4.    -   118. The method of any one of embodiments 87-117, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline after 8 weeks        of said administering, wherein the patient has a baseline        Numerical Rating Scale score of equal to or greater than 4.    -   119. The method of any one of embodiments 87-118, wherein the        patient achieves at least a 2 point improvement in itch        Numerical Rating Scale score from baseline at day 2 of said        administering.    -   120. The method of any one of embodiments 87-119, wherein said        administering of said cream formulation does not result in a        statistically significant reduction in hemoglobin or platelets.    -   121. The method of any one of embodiments 87-120, wherein said        administering of said cream formulation does not result        administration site burn.    -   122. A method of treating moderate atopic dermatitis in a human        patient comprising administering to the skin of said human        patient in need thereof, a topical formulation two times per        day, wherein said topical formulation comprises 0.75% (w/w) or        1.5% (w/w) on a free base basis of ruxolitinib, or a        pharmaceutically acceptable salt thereof.    -   123. A method of treating moderate to severe atopic dermatitis        in a human patient comprising administering to the skin of said        human patient in need thereof, a topical formulation two times        per day, wherein said topical formulation comprises 0.75% (w/w)        or 1.5% (w/w) on a free base basis of ruxolitinib, or a        pharmaceutically acceptable salt thereof.    -   124. A method of treating atopic dermatitis in a human patient        comprising administering to the skin of said human patient in        need thereof, a topical formulation two times per day, wherein        the topical formulation comprises 0.75% (w/w) or 1.5% (w/w) on a        free base basis of ruxolitinib, or a pharmaceutically acceptable        salt thereof,        -   wherein said patient has:        -   an Eczema Area and Severity Index score of ≥16 at baseline;            and        -   a Body Surface Area of atopic dermatitis involvement of ≥10%            at baseline.    -   125. The method of any one of embodiments 122-124, wherein the        topical formulation is a cream formulation.    -   126. The method of any one of embodiments 122-125, wherein the        formulation comprises 0.75% (w/w) on a free base basis of        ruxolitinib, or a pharmaceutically acceptable salt thereof.    -   127. The method of any one of embodiments 122-125, wherein the        formulation comprises 1.5% (w/w) on a free base basis of        ruxolitinib, or a pharmaceutically acceptable salt thereof.    -   128. The method of any one of embodiments 122-125, wherein the        formulation comprises 0.75% (w/w) on a free base basis of        ruxolitinib phosphate.    -   129. The method of any one of embodiments 122-125, wherein the        formulation comprises 1.5% (w/w) on a free base basis of        ruxolitinib phosphate.    -   130. The method of any one of embodiments 122-129, wherein the        patient has an itch Numerical Rating scale of score of ≥4 at        baseline.    -   131. The method of any one of embodiments 122-130, wherein the        patient has an Investigator's Global Assessment score of 3 at        baseline.    -   132. The method of any one of embodiments 122-130, wherein the        patient has an Investigator's Global Assessment score of from 3        to 4 at baseline.    -   133. The method of any one of embodiments 122-129, wherein the        patient:        -   has an Investigator's Global Assessment score of 3 at            baseline; and        -   has an itch Numerical Rating scale of score of ≥4 at            baseline.    -   134. The method of any one of embodiments 122-129, wherein the        patient:        -   has an Investigator's Global Assessment score of from 3 to 4            at baseline; and        -   has an itch Numerical Rating scale of score of ≥4 at            baseline.    -   135. The method of any one of embodiments 122-134, wherein the        patient is aged ≥12 years.    -   136. The method of any one of embodiments 122-135, wherein the        patient has a history of atopic dermatitis for at least 2 years.    -   137. The method of any one of embodiments 122-129, wherein the        patient:        -   has an Investigator's Global Assessment score of 3 at            baseline;        -   has a history of atopic dermatitis for at least 2 years; and        -   is aged ≥12 years.    -   138. The method of any one of embodiments 122-129, wherein the        patient:        -   has an Investigator's Global Assessment score of from 3 to 4            at baseline;        -   has a history of atopic dermatitis for at least 2 years; and        -   is aged ≥12 years.    -   139. The method of any one of embodiments 122-129, wherein the        patient:        -   has an Investigator's Global Assessment score of 3 at            baseline;        -   has an itch Numerical Rating scale of score of ≥4 at            baseline;        -   has a history of atopic dermatitis for at least 2 years; and        -   is aged ≥12 years.    -   140. The method of any one of embodiments 122-129, wherein the        patient:        -   has an Investigator's Global Assessment score of from 3 to 4            at baseline;        -   has an itch Numerical Rating scale of score of ≥4 at            baseline;        -   has a history of atopic dermatitis for at least 2 years; and        -   is aged ≥12 years.    -   141. The method of any one of embodiments 122-129, wherein the        patient has one or more of the following characteristics:        -   an Investigator's Global Assessment score of 3 at baseline;        -   an itch Numerical Rating scale of score of ≥4 at baseline;        -   a history of atopic dermatitis for at least 2 years; and        -   aged ≥12 years.    -   142. The method of any one of embodiments 122-129, wherein the        patient has one or more of the following characteristics:        -   an Investigator's Global Assessment score of from 3 to 4 at            baseline;        -   an itch Numerical Rating scale of score of ≥4 at baseline;        -   a history of atopic dermatitis for at least 2 years; and        -   aged ≥12 years.    -   143. The method of any one of embodiments 122-142, wherein the        patient is diagnosed with atopic dermatitis as defined by the        Hanifin and Rajika criteria.    -   144. The method of any one of embodiments 122-143, wherein said        administering is maintained for at least 2 weeks.    -   145. The method of any one of embodiments 122-143, wherein said        administering is maintained for at least 4 weeks.    -   146. The method of any one of embodiments 122-143, wherein said        administering is maintained for at least 8 weeks.    -   147. The method of any one of embodiments 122-146, wherein the        patient achieves Investigator's Global Assessment score of 0 or        1 with an improvement of at least 2 points from baseline.    -   148. The method of any one of embodiments 122-146, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 2        weeks of said administering.    -   149. The method of any one of embodiments 122-146, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 4        weeks of said administering.    -   150. The method of any one of embodiments 122-146, wherein the        patient achieves an Investigator's Global Assessment score of 0        or 1 with an improvement of at least 2 points from baseline at 8        weeks of said administering.    -   151. The method of any one of embodiments 122-150, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline.    -   152. The method of any one of embodiments 122-151, wherein the        patient achieves a statistically significant improvement in        Eczema Area and Severity Index score from baseline at week 4 of        said administering compared to a patient administered placebo        for the same period.    -   153. The method of any one of embodiments 122-152, wherein the        patient achieves a statistically significant improvement in        Eczema Area and Severity Index score from baseline at week 8 of        said administering compared to a patient administered placebo        for the same period.    -   154. The method of any one of embodiments 122-153, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 2 of said administering.    -   155. The method of any one of embodiments 122-153, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 4 of said administering.    -   156. The method of any one of embodiments 122-153, wherein the        patient achieves a 75% improvement in Eczema Area and Severity        Index score from baseline at week 8 of said administering.    -   157. The method of any one of embodiments 122-156, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline, wherein the        patient has a baseline Numerical Rating Scale score of equal to        or greater than 4.    -   158. The method of any one of embodiments 122-156, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline after 2 weeks        of said administering, wherein the patient has a baseline        Numerical Rating Scale score of equal to or greater than 4.    -   159. The method of any one of embodiments 122-156, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline after 4 weeks        of said administering, wherein the patient has a baseline        Numerical Rating Scale score of equal to or greater than 4.    -   160. The method of any one of embodiments 122-156, wherein the        patient achieves at least a 4 point improvement in improvement        in itch Numerical Rating Scale score from baseline after 8 weeks        of said administering, wherein the patient has a baseline        Numerical Rating Scale score of equal to or greater than 4.    -   161. The method of any one of embodiments 122-160, wherein the        patient achieves at least a 2 point improvement in itch        Numerical Rating Scale score from baseline at day 2 of said        administering.    -   162. The method of any one of embodiments 122-161, wherein the        patient achieves a clinically meaningful improvement in the        PROMIS Short Form—Sleep Disturbances (8b) 24-hour recall score.    -   163. The method of any one of embodiments 122-162, wherein the        patient achieves a clinically meaningful improvement in the        PROMIS Short Form—Sleep Disturbances (8b) 24-hour recall score        at Week 8.    -   164. The method of any one of embodiments 122-143, wherein:        -   the patient achieves at least a 4-point reduction in itch            Numerical Rating Scale score from baseline at week 4 of said            administering; and        -   the patient achieves an Investigator's Global Assessment            score of 0 or 1 with an improvement of at least 2 points            from baseline at week 4 of said administering.    -   165. The method of any one of embodiments 122-143, wherein:        -   the patient achieves at least a 4-point reduction in itch            Numerical Rating Scale score from baseline at week 8 of said            administering; and        -   the patient achieves an Investigator's Global Assessment            score of 0 or 1 with an improvement of at least 2 points            from baseline at week 8 of said administering.    -   166. The method of any one of embodiments 122-143, wherein:        -   the patient achieves at least a 4-point reduction in itch            Numerical Rating Scale score from baseline at week 4 of said            administering; and        -   the patient achieves a 75% improvement in Eczema Area and            Severity Index score from baseline at week 4 of said            administering.    -   167. The method of any one of embodiments 122-143, wherein:        -   the patient achieves at least a 4-point reduction in itch            Numerical Rating Scale score from baseline at week 8 of said            administering; and        -   the patient achieves a 75% improvement in Eczema Area and            Severity Index score from baseline at week 8 of said            administering.    -   168. The method of any one of embodiments 122-143, wherein:        -   the patient achieves an Investigator's Global Assessment            score of 0 or 1 with an improvement of at least 2 points            from baseline at week 4 of said administering; and        -   the patient achieves a 75% improvement in Eczema Area and            Severity Index score from baseline at week 4 of said            administering.    -   169. The method of any one of embodiments 122-143, wherein:        -   the patient achieves an Investigator's Global Assessment            score of 0 or 1 with an improvement of at least 2 points            from baseline at week 8 of said administering; and        -   the patient achieves a 75% improvement in Eczema Area and            Severity Index score from baseline at week 8 of said            administering.    -   170. The method of any one of embodiments 122-143, wherein:        -   the patient achieves at least a 4-point reduction in itch            Numerical Rating Scale score from baseline at week 4 of said            administering;        -   the patient achieves an Investigator's Global Assessment            score of 0 or 1 with an improvement of at least 2 points            from baseline at week 4 of said administering; and        -   the patient achieves a 75% improvement in Eczema Area and            Severity Index score from baseline at week 4 of said            administering.    -   171. The method of any one of embodiments 122-143, wherein:        -   the patient achieves at least a 4-point reduction in itch            Numerical Rating Scale score from baseline at week 8 of said            administering;        -   the patient achieves an Investigator's Global Assessment            score of 0 or 1 with an improvement of at least 2 points            from baseline at week 8 of said administering; and        -   the patient achieves a 75% improvement in Eczema Area and            Severity Index score from baseline at week 8 of said            administering.    -   172. The method of any one of embodiments 122-171, wherein the        patient did not use topical treatments for atopic dermatitis,        other than bland emollients, within 2 weeks of baseline; and did        not use systemic immunosuppressive or systemic immunomodulating        drugs within 4 weeks of baseline.    -   173. The method of any one of embodiments 122-172, wherein the        patient is not administered other therapeutic agents used to        treat atopic dermatitis.    -   174. The method of any one of embodiments 122-173, wherein said        the two administrations per day are at least 8 hours apart.    -   175. The method of any one of embodiments 122-174, wherein the        formulation has a pH from about 2.8 to about 3.9.    -   176. The method of any one of embodiments 122-174, wherein the        formulation has a pH from about 2.8 to about 3.6.    -   177. The method of any one of embodiments 122-176, wherein the        formulation is a solubilized cream.    -   178. The method of any one of embodiments 122-177, wherein said        administering of said formulation does not result in a        statistically significant reduction in hemoglobin or platelets.    -   179. The method of any one of embodiments 122-178, wherein said        administering of said formulation does not result administration        site burn.    -   180. A method of treating moderate atopic dermatitis in a human        patient comprising administering to the skin of said human        patient in need thereof, a topical formulation two times per        day, wherein said topical formulation comprises 1.5% (w/w) on a        free base basis of ruxolitinib, or a pharmaceutically acceptable        salt thereof.    -   181. The method of embodiment 180, wherein the ruxolitinib, or a        pharmaceutically acceptable salt thereof, is ruxolitinib        phosphate.    -   182. The method of embodiment 180, wherein the patient is aged        12 years or older.    -   183. The method of embodiment 180, wherein patient has a Body        Surface Area of atopic dermatitis involvement of from 10% to 20%        at baseline.    -   184. The method of embodiment 180, wherein the patient has an        Eczema Area and Severity Index score of ≥16 at baseline.    -   185. The method of embodiment 180, wherein the patient achieves        an Investigator's Global Assessment score of 0 or 1 with an        improvement of at least 2 points from baseline.    -   186. The method of embodiment 180, wherein the patient achieves        a 75% improvement in Eczema Area and Severity Index score from        baseline.    -   187. The method of embodiment 180, wherein the patient achieves        at least a 4 point improvement in improvement in itch Numerical        Rating Scale score from baseline, and    -   wherein the patient has a baseline Numerical Rating Scale score        of equal to or greater than 4.    -   188. The method of embodiment 180, wherein the patient achieves:        -   an Investigator's Global Assessment score of 0 or 1 with an            improvement of at least 2 points from baseline;        -   a 4 point improvement in improvement in itch Numerical            Rating Scale score from baseline, wherein the patient has a            baseline Numerical Rating Scale score of equal to or greater            than 4; and        -   a 75% improvement in Eczema Area and Severity Index score            from baseline.    -   189. The method of embodiment 180, wherein the patient achieves:        -   an Investigator's Global Assessment score of 0 or 1 with an            improvement of at least 2 points from baseline at Week 4;        -   a 4 point improvement in improvement in itch Numerical            Rating Scale score from baseline at Week 4, wherein the            patient has a baseline Numerical Rating Scale score of equal            to or greater than 4; and        -   a 75% improvement in Eczema Area and Severity Index score            from baseline at Week 4.    -   190. The method of embodiment 180, wherein the patient achieves:        -   an Investigator's Global Assessment score of 0 or 1 with an            improvement of at least 2 points from baseline at Week 8;        -   a 4 point improvement in improvement in itch Numerical            Rating Scale score from baseline at Week 8, wherein the            patient has a baseline Numerical Rating Scale score of equal            to or greater than 4; and        -   a 75% improvement in Eczema Area and Severity Index score            from baseline at Week 8.    -   191. The method of embodiment 180, wherein the patient achieves        at least a 2 point improvement in itch Numerical Rating Scale        score from baseline at day 2 of said administering.    -   192. The method of embodiment 180, wherein the patient achieves        a clinically meaningful improvement in the PROMIS Short        Form—Sleep Disturbances (8b) 24-hour recall score at Week 8.    -   193. The method of embodiment 180, wherein the formulation is a        cream formulation.    -   194. The method of embodiment 193, wherein the cream formulation        is an oil-in-water emulsion.    -   195. The method of embodiment 194, wherein the cream formulation        has a pH from about 2.8 to about 3.9.    -   196. The method of embodiment 195, wherein said administering of        said formulation does not result in a statistically significant        reduction in hemoglobin or platelets.    -   197. The method of embodiment 196, wherein said administering of        said formulation does not result in administration site burn.    -   198. A method of treating atopic dermatitis in a human patient        comprising administering to the skin of said human patient in        need thereof, a topical formulation two times per day, wherein        said topical formulation comprises 1.5% (w/w) on a free base        basis of ruxolitinib phosphate, wherein said patient:        -   is aged 12 years or older;        -   has a Body Surface Area of atopic dermatitis involvement of            from 10% to 20% at baseline; and        -   has an Investigator's Global Assessment score of 3 at            baseline.    -   199. The method of embodiment 198, wherein the patient achieves        Investigator's Global Assessment score of 0 or 1 with an        improvement of at least 2 points from baseline.    -   200. The method of embodiment 198, wherein the patient achieves        a 75% improvement in Eczema Area and Severity Index score from        baseline.    -   201. The method of embodiment 198, wherein the patient achieves        at least a 4 point improvement in improvement in itch Numerical        Rating Scale score from baseline, and    -   wherein the patient has a baseline Numerical Rating Scale score        of equal to or greater than 4.    -   202. The method of embodiment 198, wherein the patient achieves:        -   an Investigator's Global Assessment score of 0 or 1 with an            improvement of at least 2 points from baseline;        -   a 4 point improvement in improvement in itch Numerical            Rating Scale score from baseline, wherein the patient has a            baseline Numerical Rating Scale score of equal to or greater            than 4; and        -   a 75% improvement in Eczema Area and Severity Index score            from baseline.    -   203. The method of embodiment 198, wherein the patient achieves:        -   an Investigator's Global Assessment score of 0 or 1 with an            improvement of at least 2 points from baseline at Week 4;        -   a 4 point improvement in improvement in itch Numerical            Rating Scale score from baseline at Week 4, wherein the            patient has a baseline Numerical Rating Scale score of equal            to or greater than 4; and        -   a 75% improvement in Eczema Area and Severity Index score            from baseline at Week 4.    -   204. The method of embodiment 198, wherein the patient achieves:        -   an Investigator's Global Assessment score of 0 or 1 with an            improvement of at least 2 points from baseline at Week 8;        -   a 4 point improvement in improvement in itch Numerical            Rating Scale score from baseline at Week 8, wherein the            patient has a baseline Numerical Rating Scale score of equal            to or greater than 4; and        -   a 75% improvement in Eczema Area and Severity Index score            from baseline at Week 8.    -   205. The method of embodiment 198, wherein the formulation is a        cream formulation.    -   206. The method of embodiment 205, wherein the cream formulation        is an oil-in-water emulsion.    -   207. A method of reducing itch in a human patient with atopic        dermatitis, comprising administering to the skin of said human        patient in need thereof, a cream formulation two times per day,        wherein said cream formulation comprises 1.5% (w/w) on a free        base basis of ruxolitinib, or a pharmaceutically acceptable salt        thereof;        -   wherein said patient achieves a statistically significant            reduction in itch Numerical Rating Scale score from baseline            within 36 hours of said administering.    -   208. A method of reducing itch in a human patient with atopic        dermatitis, comprising administering to the skin of said human        patient in need thereof, a cream formulation two times per day,        wherein said cream formulation comprises 1.5% (w/w) on a free        base basis of ruxolitinib, or a pharmaceutically acceptable salt        thereof, wherein the patient achieves at least a 1 point        reduction in itch Numerical Rating Scale score by day 2 of said        administering.    -   209. The method of embodiment 208, wherein the ruxolitinib, or a        pharmaceutically acceptable salt thereof, is ruxolitinib        phosphate.    -   210. The method of embodiment 208, wherein the patient achieves        a statistically significant reduction in the itch Numerical        Rating Scale score from baseline within 12 hours of said        administering.    -   211. The method of embodiment 208, wherein the patient achieves        a 2 point improvement in itch Numerical Rating Scale score        within 12 hours of said administering.    -   212. The method of embodiment 208, wherein the patient achieves        a 2 point improvement in itch Numerical Rating Scale score        within 36 hours of said administering.    -   213. The method of embodiment 208, wherein the patient achieves        a 4 point improvement in itch Numerical Rating Scale score        within 36 hours of said administering.    -   214. The method of embodiment 208, wherein the patient achieves        at least a 2 point reduction in itch Numerical Rating Scale        score at week 1 of said administering.    -   215. The method of embodiment 208, wherein the patient achieves        at least a 3 point reduction in itch Numerical Rating Scale        score at week 3 of said administering.    -   216. The method of embodiment 208, wherein the patient achieves        a minimal clinically important difference in itch Numerical        Rating Scale score within 36 hours of said administering,        wherein said minimal clinically important difference in itch        Numerical Rating Scale score is a 2 to 3 point reduction in itch        Numerical Rating Scale score versus baseline, wherein the        patient has a baseline Numerical Rating Scale score of equal to        or greater than 2.    -   217. The method of embodiment 208, wherein the patient achieves        a clinically relevant improvement in itch Numerical Rating Scale        score within 36 hours of said administering,    -   wherein said clinically relevant improvement in itch Numerical        Rating Scale score is a ≥4 point reduction in itch Numerical        Rating Scale score versus baseline, wherein the patient has a        baseline Numerical Rating Scale score of equal to or greater        than 4.    -   218. The method of embodiment 208, wherein said patient is aged        12 or older.    -   219. The method of embodiment 218, wherein said patient has a        Body Surface Area (BSA) of atopic dermatitis involvement        (excluding scalp) of 3% to 20% at baseline.    -   220. The method of embodiment 219, wherein said patient has an        Investigator's Global Assessment score of 2 to 3 at baseline.    -   221. The method of embodiment 220, wherein the patient has been        diagnosed with atopic dermatitis for at least 2 years.    -   222. The method of embodiment 221, wherein the patient is        diagnosed with atopic dermatitis as defined by the Hanifin and        Rajika criteria.    -   223. The method of embodiment 222, wherein the patient did not        use topical treatments for atopic dermatitis, other than        emollients, within 2 weeks of baseline.    -   224. The method of embodiment 208, wherein the patient achieves        at least a 4 point reduction in itch Numerical Rating Scale        score from baseline at week 2 of said administering.    -   225. The method of embodiment 208, wherein the patient achieves        at least a 4 point reduction in itch Numerical Rating Scale        score from baseline at week 4 of said administering.    -   226. The method of embodiment 208, wherein the patient achieves        at least a 4 point reduction in itch Numerical Rating Scale        score from baseline at week 8 of said administering.    -   227. The method of embodiment 208, wherein the patient achieves        a 75% improvement in Eczema Area and Severity Index score from        baseline at week 2 of said administering.    -   228. The method of embodiment 208, wherein the patient achieves        a 75% improvement in Eczema Area and Severity Index score from        baseline at week 4 of said administering.    -   229. The method of embodiment 208, wherein the patient achieves        a 75% improvement in Eczema Area and Severity Index score from        baseline at week 8 of said administering.    -   230. The method of embodiment 208, wherein the patient achieves        an Investigator's Global Assessment score of 0 or 1 with an        improvement of at least 2 points from baseline at week 2 of said        administering.    -   231. The method of embodiment 208, wherein the patient achieves        an Investigator's Global Assessment score of 0 or 1 with an        improvement of at least 2 points from baseline at week 4 of said        administering.    -   232. The method of embodiment 208, wherein the patient achieves        an Investigator's Global Assessment score of 0 or 1 with an        improvement of at least 2 points from baseline at week 8 of said        administering.    -   233. The method of embodiment 209, wherein the cream formulation        is an oil-in-water emulsion.    -   234. The method of embodiment 233, wherein the cream formulation        has a pH from about 2.8 to about 3.6.    -   235. A method of reducing itch in a human patient with atopic        dermatitis, comprising administering to the skin of said human        patient in need thereof, a cream formulation two times per day,        wherein said cream formulation comprises 1.5% (w/w) on a free        base basis of ruxolitinib phosphate;        -   wherein the patient:            -   is aged 12 years or older;            -   has an Investigator's Global Assessment score of 2 to 3                at baseline;            -   has a Body Surface Area of atopic dermatitis involvement                (excluding scalp) of 3% to 20% at baseline; and            -   achieves a minimal clinically important difference in                itch Numerical Rating Scale score within 36 hours of                said administering, wherein said minimal clinically                important difference in the itch Numerical Rating Scale                score is a 2 to 3 point reduction in itch Numerical                Rating Scale score versus baseline, wherein the patient                has a baseline itch Numerical Rating Scale score of ≥2.    -   236. A method of reducing itch in a human patient with atopic        dermatitis, comprising administering to the skin of said human        patient in need thereof, a cream formulation two times per day,        wherein said cream formulation comprises 1.5% (w/w) on a free        base basis of ruxolitinib phosphate;        -   wherein the patient:            -   is aged 12 years or older;            -   has an Investigator's Global Assessment score of 2 to 3                at baseline;            -   has a Body Surface Area of atopic dermatitis involvement                (excluding scalp) of 3% to 20% at baseline; and            -   achieves a clinically relevant improvement in itch                Numerical Rating Scale score within 36 hours of said                administering, wherein the clinically relevant                improvement in the itch Numerical Rating Scale score is                a ≥4 point reduction in the itch Numerical Rating Scale                score versus baseline, wherein the patient has a                baseline Numerical Rating Scale score of ≥4.    -   237. A method of treating atopic dermatitis in a human patient,        comprising administering to the skin of the human patient in        need thereof, a cream formulation two times per day, wherein the        cream formulation comprises 0.75% (w/w) on a free base basis of        ruxolitinib, or a pharmaceutically acceptable salt thereof.    -   238. The method of embodiment 237, wherein the ruxolitinib, or a        pharmaceutically acceptable salt thereof, is ruxolitinib        phosphate.    -   239. The method of embodiment 237, wherein the patient achieves        Investigator's Global Assessment score of 0 or 1 with an        improvement of at least 2 points from baseline.    -   240. The method of embodiment 237, wherein the patient achieves        an Investigator's Global Assessment score of 0 or 1 with an        improvement of at least 2 points from baseline at week 2 of the        administering.    -   241. The method of embodiment 237, wherein the patient achieves        an Investigator's Global Assessment score of 0 or 1 with an        improvement of at least 2 points from baseline at week 4 of the        administering.    -   242. The method of embodiment 237, wherein the patient achieves        an Investigator's Global Assessment score of 0 or 1 with an        improvement of at least 2 points from baseline at week 8 of the        administering.    -   243. The method of embodiment 237, wherein the patient achieves        a 75% improvement in Eczema Area and Severity Index score from        baseline.    -   244. The method of embodiment 237, wherein the patient achieves        a 75% improvement in Eczema Area and Severity Index score from        baseline at week 2 of the administering.    -   245. The method of embodiment 237, wherein the patient achieves        a 75% improvement in Eczema Area and Severity Index score from        baseline at week 4 of the administering.    -   246. The method of embodiment 237, wherein the patient achieves        a 75% improvement in Eczema Area and Severity Index score from        baseline at week 8 of the administering.    -   247. The method of embodiment 237, wherein the patient achieves        at least a 4 point improvement in improvement in itch Numerical        Rating Scale score from baseline.    -   248. The method of embodiment 237, wherein the patient achieves        at least a 4 point improvement in improvement in itch Numerical        Rating Scale score from baseline, and    -   wherein the patient has a baseline Numerical Rating Scale score        of equal to or greater than 4.    -   249. The method of embodiment 237, wherein the patient achieves        at least a 4 point improvement in improvement in itch Numerical        Rating Scale score from baseline at week 2 of the administering,        and wherein the patient has a baseline Numerical Rating Scale        score of equal to or greater than 4.    -   250. The method of embodiment 237, wherein the patient achieves        at least a 4 point improvement in improvement in itch Numerical        Rating Scale score from baseline at week 4 of the administering,        and wherein the patient has a baseline Numerical Rating Scale        score of equal to or greater than 4.    -   251. The method of embodiment 237, wherein the patient achieves        at least a 4 point improvement in improvement in itch Numerical        Rating Scale score from baseline at week 8 of the administering,        and wherein the patient has a baseline Numerical Rating Scale        score of equal to or greater than 4.    -   252. The method of embodiment 237, wherein the patient achieves        a minimal clinically important difference in itch Numerical        Rating Scale score within 36 hours of the administering wherein        the minimal clinically important difference in itch Numerical        Rating Scale score is a 2 to 3 point reduction in itch Numerical        Rating Scale score versus baseline, wherein the patient has a        baseline Numerical Rating Scale score of equal to or greater 2.    -   253. The method of embodiment 237, wherein the patient achieves        a clinically relevant improvement in itch Numerical Rating Scale        score within 36 hours of the administering,    -   wherein the clinically relevant improvement in itch Numerical        Rating Scale score is a ≥4 point reduction in itch Numerical        Rating Scale score versus baseline, wherein the patient has a        baseline Numerical Rating Scale score of equal to or greater 4.    -   254. The method of embodiment 237, wherein the administering is        maintained for at least 2, 4, or 8 weeks.    -   255. The method of embodiment 237, wherein the patient is aged        12 or older.    -   256. The method of embodiment 255, wherein the patient has a        Body Surface Area (BSA) of atopic dermatitis involvement        (excluding scalp) of 3% to 20% at baseline.    -   257. The method of embodiment 256 wherein the patient has an        Investigator's Global Assessment score of 2 to 3 at baseline.    -   258. The method of embodiment 257, wherein the patient has been        diagnosed with atopic dermatitis for at least 2 years.    -   259. The method of embodiment 258, wherein the patient is        diagnosed with atopic dermatitis as defined by the Hanifin and        Rajika criteria.    -   260. The method of embodiment 259, wherein the patient did not        use topical treatments for atopic dermatitis, other than        emollients, within 2 weeks of baseline.    -   261. The method of embodiment 238, wherein the cream formulation        is an oil-in-water emulsion.    -   262. The method of embodiment 261, wherein the cream formulation        is a solubilized cream.    -   263. The method of embodiment 262, wherein the cream formulation        has a pH from about 2.8 to about 3.6.    -   264. A method of treating atopic dermatitis in a human patient,        comprising administering to the skin of the human patient in        need thereof, a cream formulation two times per day, wherein the        cream formulation comprises 0.75% (w/w) on a free base basis of        ruxolitinib, or a pharmaceutically acceptable salt thereof,        wherein the patient:        -   is aged 12 years or older;        -   has an Investigator's Global Assessment score of 2 to 3 at            baseline;        -   has a Body Surface Area of atopic dermatitis involvement            (excluding scalp) of 3% to 20% at baseline; and        -   achieves an Investigator's Global Assessment score of 0 or 1            with an improvement of at least 2 points from baseline at            week 8 of the administering.    -   265. A method of treating atopic dermatitis in a human patient,        comprising administering to the skin of the human patient in        need thereof, a cream formulation two times per day, wherein the        cream formulation comprises 0.75% (w/w) on a free base basis of        ruxolitinib, or a pharmaceutically acceptable salt thereof,        wherein the patient:        -   is aged 12 years or older;        -   has an Investigator's Global Assessment score of 2 to 3 at            baseline;        -   has a Body Surface Area of atopic dermatitis involvement            (excluding scalp) of 3% to 20% at baseline; and        -   achieves a 75% improvement in Eczema Area and Severity Index            score from baseline at week 8 of the administering.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters, which can be changed or modified to yield essentially thesame results. In some embodiments, the present disclosure providespharmaceutical formulations comprising the components specified in theexample formulations (e.g., Example 3), wherein the components arepresent in about the amounts in Tables 2-5.

EXAMPLES Example 1: Preparation of Oil-In-Water Cream Formulations ofRuxolitinib (INCB018424) Phosphate

First, in order to determine the solubility of ruxolitinib (free base)or its 1:1 phosphate salt, approximately 5 mL of a potential solvent wasadded to approximately 50 mg of the API or its salt at room temperature.The mixtures were suspended and rotated on a wheel. If the mixturesbecame clear solutions, more solid material was added. The suspensionswere then suspended over 24 hours. The samples were filtered through 0.2micron filters. The liquid portions were collected and diluted with50/50 water methanol/water. The concentrations of the diluted sampleswere analyzed by HPLC. When the free base or salt was fairly insoluble,the results are approximate only.

TABLE 1 Solubility of Phosphate Solubility of Free Potential SolventSalt (mg/mL) Base (mg/mL) Water 2.7 2.0 pH 4, citric buffer, 0.1M 1.51.1 pH 6, citric buffer, 0.1M 0.2 0.15 Ethanol 7.3 5.5 Isopropanol 0.60.45 Benzyl alcohol 3 2.3 Propylene glycol 24 18.2 PEG 200 23 17.4 PEG300 14 10.6 Glycerin 11 8.3 Transcutol 10 7.6 Trolamine 51 38.6Water/PEG 200 23 17.4 (50/50) Water/glyercin 21 15.9 (50/50)Water/glycerin/trolamine 18 13.6 (40/40/20) Isopropyl myristate <0.10.08 Isosorbide dimethyl 0.4 0.3 ether Mineral oil <0.1 0.08 Olelylalcohol 0.1 0.08 Dimethicone <0.2 0.15 C₁₂₋₁₅ alcohol benzoate <0.2 0.15Caprylic triglyceride <0.2 0.15

An oil-in-water cream formulation was prepared for 1:1 ruxolitinibphosphoric acid salt at 0.5, 1.0 and 1.5% by weight of the formulation(free base equivalent). The compositions for a 15 gram tube are providedin Table 2 below. The formulation for three strengths were identicalexcept for adjustments to the purified water quantity based on theamount of active ingredient. All excipients used in the formulation werecompendial grade (i.e., USP/NF or BP) or are approved for use in topicalproducts.

The quantitative formulae for representative 400 kg batches of the creamformulation at 0.5, 1.0 and 1.5% are also provided in Tables 3, 4, and5, respectively.

The oil-in-water cream formulations were synthesized according to thefollowing procedure at either a 3.5 kg or 400 kg scale (when made at a3.5 kg batch size, the amounts in Tables 3-5 were scaled appropriately).Some batches were subject to minor changes associated with scale-up,such as the size of mixing vessels and mixers. Generally, overhead mixerwith high and low shear mixing blades are suitable for the process.

Procedure

-   -   1. A paraben phase was prepared by mixing methyl and propyl        parabens with a portion of the propylene glycol (see % in Tables        2-5).    -   2. Next, a xanthan gum phase was prepared by mixing xanthan gum        with propylene glycol (see % in Table 2-5).    -   3. An oil phase was then prepared by mixing light mineral oil,        glyceryl stearate, polysorbate 20, white petrolatum, cetyl        alcohol, stearyl alcohol, dimethicone and medium chain        triglycerides. The phase is heated to 70-80° C. to melt and form        a uniform mixture.    -   4. The aqueous phase was next prepared by mixing purified water,        polyethylene glycol, and disodium EDTA. The phase is heated to        70-80° C.    -   5. The aqueous phase of step 4, paraben phase of step 1, and        Example 2 (phosphate salt of API) were combined to form a        mixture.    -   6. The xanthan gum phase from step 2 was then added to the        mixture from step 5.    -   7. The oil phase from step 3 was then combined under high shear        mixing with the mixture from step 6 to form an emulsion.    -   8. Phenoxyethanol was then added to the emulsion from step 7.        Mixing was continued, and then the product was cooled under low        shear mixing.

TABLE 2 Percentage of FORMULA Total Grams/ PHASE COMPONENT Function (%w/w) Tube Paraben Propylene Solvent 10.00 1.5 Glycol USP Methyl ParabenAntimicrobial 0.10 0.015 NF preservative Propyl Paraben Antimicrobial0.05 0.0075 NF preservative Xanthan Propylene Solvent 5.00 0.75 GumGlycol USP Xanthan Gum Suspending, 0.40 0.06 NF stabilizing, viscosity-increasing agent Oil Light Mineral Emollient, 4.00 0.6 Oil NF solventGlyceryl Stearate Emulsifier 3.00 0.45 SE Polysorbate 20 Emulsifying/1.25 0.1875 NF stabilizing agent White Petrolatum Occlusive agent 7.001.05 USP Cetyl Alcohol Stiffening agent, 3.00 0.45 NF consistencyimprover Stearyl Alcohol Stiffening agent 1.75 0.2625 NF Dimethicone 360Skin protectant 1.00 0.15 NF Medium Chain Emollient, 5.00 0.75Triglyceride NF solvent Aqueous/ Purified Water Solvent 50.24- 7.536-Active USP 48.92 7.338 Edetate Chelating agent 0.05 0.0075 Disodium USPPolyethylene Solvent 7.00 1.05 Glycol USP Example 2 * Active 0.66-1.980.099- 0.297 Final Phenoxyethanol Antimicrobial 0.50 0.075 BPpreservative Total 100.00% 15

TABLE 3 Ingredient Kilograms Percentage (w/w) Ruxolitinib phosphate 2.64(phosphate salt)/ 0.66 (phosphate salt)/ 2.0 (free base) 0.5 (free base)Propylene Glycol USP 40.0 10.00 Methyl Paraben NF 0.4 0.10 PropylParaben NF 0.2 0.05 Propylene Glycol USP 20.0 5.00 Xanthan Gum NF 1.60.40 Light Mineral Oil NF 16.0 4.00 Glyceryl Stearate SE 12.0 3.00Polysorbate 20 NF 5.0 1.25 White Petrolatum USP 28.0 7.00 Cetyl alcoholNF 12.0 3.00 Stearyl alcohol NF 7.0 1.75 Dimethicone 360 NF 4.0 1.00Medium Chain 20.0 5.00 Triglycerides NF Purified Water USP 201 50.25(approximate) Edetate Disodium USP 0.2 0.05 Polyethylene Glycol USP 28.07.00 Phenoxyethanol BP 2.0 0.5 Total (approximate) 400.0 100

TABLE 4 Ingredient Kilograms Percentage (w/w) Ruxolitinib phosphate 5.28(phosphate salt)/ 1.32 (phosphate salt)/ 4.0 (free base) 1.00 (freebase) Propylene Glycol USP 40.0 10.00 Methyl Paraben NF 0.4 0.10 PropylParaben NF 0.2 0.05 Propylene Glycol USP 20.0 5.00 Xanthan Gum NF 1.60.40 Light Mineral Oil NF 16.0 4.00 Glyceryl Stearate SE 12.0 3.00Polysorbate 20 NF 5.0 1.25 White Petrolatum USP 28.0 7.00 Cetyl alcoholNF 12.0 3.00 Stearyl alcohol NF 7.0 1.75 Dimethicone 360 NF 4.0 1.00Medium Chain 20.0 5.00 Triglycerides NF Purified Water USP 198.5 49.6(approximate) Edetate Disodium USP 0.2 0.05 Polyethylene Glycol USP 28.07.00 Phenoxyethanol BP 2.0 0.5 Total (approximate) 400.0 100

TABLE 5 Ingredient Kilograms Percentage (w/w) Ruxolitinib phosphate 7.92(phosphate salt)/ 1.98 (phophate salt)/ 6.0 (free base) 1.5 (free base)Propylene Glycol USP 40.0 10.00 Methyl Paraben NF 0.4 0.10 PropylParaben NF 0.2 0.05 Propylene Glycol USP 20.0 5.00 Xanthan Gum NF 1.60.40 Light Mineral Oil NF 16.0 4.00 Glyceryl Stearate SE 12.0 3.00Polysorbate 20 NF 5.0 1.25 White Petrolatum USP 28.0 7.00 Cetyl alcoholNF 12.0 3.00 Stearyl alcohol NF 7.0 1.75 Dimethicone 360 NF 4.0 1.00Medium Chain 20.0 5.00 Triglycerides NF Purified Water USP 195.5 48.9(approximate) Edetate Disodium USP 0.2 0.05 Polyethylene Glycol USP 28.07.00 Phenoxyethanol BP 2.0 0.5 Total (approximate) 400.0 100

More consistent batches at larger scales (e.g., 140 kg) could beobtained by adding ruxolitinib phosphate gradually to the aqueous phaseand then combining with the other phases. Similarly, more consistentbatches could be obtained by slower cooling (e.g., by using roomtemperature water in the outer jacket of the reactor, rather than lowertemperature water.

Table 5A shows the 0.75% and 1.5% ruxolitinib cream formulation used inExample 3.

TABLE 5A 0.75% Cream 1.5% Cream g per 60 g g per 60 g Component wt %tube wt % tube Ruxolitinib Phosphate 0.99 0.594 1.98 1.188 (0.751))(1.50^(b)) Propylene Glycol 15.0 9.00 15.0 9.00 Methylparaben 0.10 0.060.10 0.06 Propylparaben 0.05 0.03 0.05 0.03 Xanthan Gum 0.40 0.24 0.400.24 Light Mineral Oil 4.00 2.40 4.00 2.40 Glyceryl Stearate SE 3.001.80 3.00 1.80 Polysorbate 20 1.25 0.75 1.25 0.75 White Petrolatum 7.004.20 7.00 4.20 Cetyl Alcohol 3.00 1.80 3.00 1.80 Stearyl Alcohol 1.751.05 1.75 1.05 Dimethicone 360 1.00 0.60 1.00 0.60 Triglycerides, 5.003.00 5.00 3.00 Medium Chain Purified Water 49.91 29.95 48.92 29.36Edetate Disodium 0.05 0.03 0.05 0.03 Polyethylene Glycol 200 7.00 4.207.00 4.20 Phenoxyethanol 0.50 0.30 0.50 0.30 Total 100% 60 g 100% 60 g

The batches were tested for stability at 25° C. and found to be stableup to 24 months with a pH consistent with the pH range described supra(see Table 7, 9, 11, 12, 13, 15, 17, and 19 in U.S. Patent Publ. No.2015/0250790, which is incorporated herein by reference in itsentirety). The viscosity of the cream formulations (e.g., containing0.75% or 1.5% ruxolitinib phosphate on a free base basis) had aviscosity of ≥17,000 cPs on release and a shelf-life viscosity of≥10,000 cPs.

Example 2: Phase 2, Randomized, Dose-Ranging, Vehicle-Controlled andTriamcinolone 0.1% Cream—Controlled Study to Evaluate the Safety andEfficacy of Ruxolitinib (INCB018424) Phosphate Cream Applied Topicallyto Adults with Atopic Dermatitis

This was a randomized, vehicle- and active (triamcinolone 0.1%cream)-controlled study in subjects with mild to moderate atopicdermatitis (AD). The study was double-blinded for vehicle, ruxolitinibcream doses, and active control. 307 subjects were randomized1:1:1:1:1:1 to 1.5% ruxolitinib cream BID, 1.5% ruxolitinib cream QD,0.5% ruxolitinib cream QD, 0.15% ruxolitinib cream QD, vehicle BID, andactive control (triamcinolone 0.1% cream BID) and stratified by EASIscore (≤7 and >7). The ruxolitinib in the ruxolitinib cream was presentas ruxolitinib phosphate with the percentages as % w/w on a free basebasis. The ruxolitinib cream formulations were oil-in-water creamformulations prepared as described in Example 1 (see also U.S. PatentPubl. No. 2015/0250790), which is incorporated herein by reference inits entirety.

Subjects receiving QD regimens applied vehicle at the eveningapplication. Subjects received blinded study drug for 8 weeks. Subjectswere randomized to triamcinolone applied triamcinolone 0.1% cream BIDfor 4 weeks and vehicle cream for 4 weeks to not exceed the allowabletriamcinolone application duration.

1.5% ruxolitinib cream, 0.5% ruxolitinib cream, and 0.15% ruxolitinibcream were supplied and applied topically as a thin film to the affectedareas in the morning and in the evening at least 1 hour before bedtime.For each 1% of BSA (palm with fingers) to be treated with study drug,approximately 2 inches (5 cm) of study drug were used. Subjects were tobe advised to limit use to no more than 1 tube per application. Ifsunscreen, makeup, or other cream were to be applied to the areas to betreated, subjects were to be instructed to wash the treatment areas withmild soap and water and pat dry before application of study drug. Ifused, topical anti infectives or other topical treatments were to beavoided for at least 1 hour before and after application of study drugto an area. Subjects were to be cautioned to avoid excessive exposure toeither natural or artificial sunlight (including tanning booths, sunlamps, etc.) and, when outdoors, were to be advised to wearloose-fitting clothing that protects the treated area from the sun.

Vehicle cream was matching in appearance to the ruxolitinib creams,except it did not contain active drug. Vehicle cream and triamcinolone0.1% cream were applied in the same manner as ruxolitinib cream.Triamcinolone 0.1% cream treatment of 4 weeks was followed by vehicletreatment for 4 weeks. Subjects receiving QD regimens of ruxolitinibcream received vehicle cream at the evening application.

At Week 8, subjects who meet criteria received open-label treatment with1.5% ruxolitinib cream BID for 4 weeks.

Subjects who developed additional areas of AD after the initiation oftreatment were allowed to treat these additional areas (except the faceand intertriginous areas) provided the total treated BSA did not exceed20% and there are no safety concerns regarding the additionalapplication of study drug.

The study population were men or women, aged 18 to 70 years, who hadbeen diagnosed with atopic dermatitis (AD) for at least 2 years, with anInvestigator's Global Assessment (IGA) score of 2 to 3, and body surfacearea (BSA) involvement (excluding the face and intertriginous areas) of3% to 20%.

Subjects who met all of the following key inclusion criteria could beincluded in the study: (i) men and women aged 18 to 70 years, inclusive;(ii) diagnosed with AD as defined by the Hanifin and Rajka criteria;(iii) history of AD for at least 2 years; (iv) an IGA score of 2 to 3 atscreening and baseline; (v) BSA of AD involvement, excluding the faceand intertriginous areas, of 3% to 20% at screening and baseline; and(vi) agreement to discontinue all agents used to treat AD from screeningthrough the final follow up visit.

Subjects who met any of the following key exclusion criteria wereexcluded from the study: (i) evidence of active acute or chronicinfections; (ii) use of topical treatments for AD (other than blandemollients) within 2 weeks of baseline; (iii) use of systemicimmunosuppressive or immunomodulating drugs (e.g., oral or injectablecorticosteroids, methotrexate, cyclosporine, mycophenolate mofetil,azathioprine) within 4 weeks or 5 half-lives of baseline (whichever islonger); (iv) subjects with other dermatologic disease besides AD whosepresence or treatments could complicate the assessment of disease (e.g.,psoriasis); (v) a history of other diseases besides dermatologicdisorders (e.g., other autoimmune diseases) taking treatments that couldcomplicate assessments; (vi) subjects with cytopenias at screening,defined as leukocytes <3.0×10⁹/L, neutrophils <lower limit of normal,hemoglobin <10 g/dL. Lymphocytes <0.8×109/L, platelets <100×109/L; (vii)subjects with severely impaired liver function (Child-Pugh Class C) orend-stage renal disease on dialysis or at least 1 of the following:serum creatinine >1.5 mg/dL, alanine aminotransferase or aspartateaminotransferase ≥1.5×upper limit of normal; (viii) subjects takingpotent systemic cytochrome P450 3A4 inhibitors or fluconazole within 2weeks or 5 half-lives, whichever is longer, before the baseline visit(topical agents with limited systemic availability are permitted); and(ix) subjects who have previously received Janus kinase inhibitors,systemic or topical (e.g., ruxolitinib, tofacitinib, baricitinib,filgotinib, lestaurtinib, or pacritinib).

The primary endpoint of the study was the percentage change frombaseline in EASI score at Week 4 in subjects treated with 1.5%ruxolitinib cream BID compared with subjects treated with vehicle creamBID.

Secondary endpoints included the mean percentage change from baseline inEASI score at Week 4 in subjects treated with ruxolitinib cream comparedwith subjects treated with vehicle cream BID; the mean percentage changefrom baseline in EASI score at Week 4 in subjects treated withruxolitinib cream compared with subjects treated with triamcinolone 0.1%cream BID; the mean percentage change from baseline in EASI score atWeek 2 and Week 8; the proportion of subjects who achieve a ≥50%improvement from baseline in EASI (EASI-50) at Weeks 2, 4, and 8;assessment of dose response based on percentage change from baseline inEASI score at Week 4; time to achieve EASI-50; proportion of subjectsachieving IGA score of 0 to 1 who have an improvement of ≥2 points frombaseline at Weeks 2, 4, and 8; the mean change from baseline in the ItchNumerical Rating Scale (NRS) score at Weeks 2, 4, and 8; and safety andtolerability assessed by monitoring the frequency, duration, andseverity of adverse events (AEs); performing physical examinations;collecting vital signs; and collecting laboratory data for hematology,serum chemistry, and urinalysis.

Other secondary endpoints included change from baseline in quality oflife based on the Skindex-16 (overall, each question, and specifiedgroupings) at Weeks 2, 4, 8, 10, and 12. Skindex-16 (Atherton P J, etal, Support Care Cancer. 2012 August; 20(8): 1729-1735) is a 16-questionquality-of-life assessment that asks how much the subject has beenbothered by various aspects of their skin condition during the pastweek. Patients answered questions regarding the effect of various ADsymptoms during the past week on a scale of 0 (never bothered) to 6(always bothered). Patients were assessed at baseline and Weeks 2, 4, 8,10, and 12.

Results

Patient demographics are shown in Table 6. Baseline clinicalcharacteristics are shown in Table 7. Skindex-16 overall score was3.7±1.3 at baseline.

TABLE 6 Demographic Total (N = 307) Age, median (range), years 35.0(18.0-70.0) Female, n (%) 168 (54.7) Race, n (%) White 172 (56.0) Black85 (27.7) Asian 41 (13.4) Other 9 (2.9)

TABLE 7 Clinical Characteristic Total (N = 307) BSA, mean ± SD, % 9.6 ±5.4 Baseline EASI, mean ± SD 8.4 ± 4.7 ≤7, n (%) 147 (47.9) ≤7, n (%)159 (51.8) Missing, n (%) 1 (0.3) Baseline IGA, n (%) 2 95 (31) 3 210(69) Itch NRS score, * mean ± SD 6.0 ± 2.1 Duration of disease, median(range), years 20.8 (0.1-66.1) Number of flares in last 12 months, mean± SD  7.3 ± 23.3

In Figures showing a triamcinolone result, the triamcinolone (TAC) armreceived 0.1% triamcinolone cream through Week 4 and vehicle thereafter.

As shown in FIG. 1 , ruxolitinib cream showed significant improvement ofEASI scores in a dose- and time-dependent manner across allconcentrations compared to vehicle control. As shown in FIG. 2 , 1.5%ruxolitinib cream showed the highest efficacy among all treatment arms(across all efficacy endpoints), while 1.5% ruxolitinib cream BIDdemonstrated noninferiority to triamcinolone (TAC) in EASI scores (Weeks2 and 4) with numerically greater rates of improvement.

Further, increasing numbers of patients achieved EASI-75 (at least a 75%improvement in EASI from baseline) in a dose- and time-dependent manner(see FIG. 3 ) with more patients achieving EASI-75 with 1.5% ruxolitinibcream BID at week 4 than with 0.1% TAC.

As shown in FIG. 4 , ruxolitinib cream demonstrated significantimprovement in IGA response (an IGA responder was a patient achieving anIGA score of 0-1 with an improvement of ≥2 points from baseline) in adose- and time-dependent manner. Further, 1.5% ruxolitinib cream BIDshowed significantly more IGA responders vs. vehicle at weeks 4 and 8(FIG. 4 ) and greater response than 0.1% TAC at week 4.

As shown in FIG. 5 , transitioning to 1.5% ruxolitinib cream BID at week8 was associated with substantial improvement in EASI scores. Similarly,switching to 1.5% ruxolitinib cream BID at week 8 was associated withsubstantial improvement in all treatment arm in IGA response (see FIG. 6).

Further, as shown in FIG. 7 , ruxolitinib cream was associated with arapid and sustained reduction in itch NRS scores (NRS score has a rangeof 0-10 with 0 being no itch and 10 being the worst possible itch). Inparticular, as shown in FIG. 8 and Table 8, significant reductions initch NRS scores were observed with 1.5% ruxolitinib cream BID within 36hours of first application (i.e., after 2 days) vs. vehicle (−1.8 vs.0.2; p<0.0001). Further, as shown in FIG. 9 and Table 8, transitioningto 1.5% ruxolitinib cream BID at week 8 was associated with additionaland sustained improvement in itch.

Clinically meaningful reductions in itch NRS scores were observed within36 hours after first application of 1.5% ruxolitinib cream BID versusvehicle (−1.8 vs −0.2; P<0.0001). Decreases in itch NRS scores notedwithin the first 2 weeks of treatment for all ruxolitinib cream regimenswere sustained through the double-blind period. At Week 4, both 1.5%ruxolitinib cream regimens produced a more pronounced alleviation initch (mean percent change from baseline, −64.6 for 1.5% BID and −54.0for 1.5% QD) compared with triamcinolone (−50.3); the difference wasstatistically significant for 1.5% ruxolitinib BID versus triamcinoloneby mean change from baseline (—4.0 vs −2.5, respectively; P=0.003).Improvements from baseline in itch NRS scores were treatment regimendependent, with 68.5% mean improvement in patients treated with 1.5%ruxolitinib cream BID at Week 8, which was significantly better thanvehicle (17.6%; P<0.0001).

In patients eligible for CRI analysis (baseline itch NRS of ≥4; n=232),a considerably higher proportion of patients on ruxolitinib creamachieved CRI response after just a single day of therapy than those onvehicle (Day 2 response rates for 1.5% ruxolitinib cream BID vs vehicle,10.5% vs 2.9%); Day 4 response rates for 1.5% ruxolitinib cream BID andvehicle were 26.3% and 2.9, respectively (P<0.05). At Week 2,significantly more patients achieved CRI with 1.5% ruxolitinib BID(47.5%; P<0.001), 1.5% ruxolitinib QD (32.4%; P<0.01), and 0.5%ruxolitinib QD (25.0%; P<0.05) versus vehicle (5.4%; FIG. 1 ). Responserates observed with 1.5% ruxolitinib cream BID at Week 2 were alsosignificantly higher compared with triamcinolone (19.4%, P<0.05).Cumulative incidence rates for time to first CRI response weresubstantially higher in all ruxolitinib cream groups (log-rank P<0.001)versus vehicle. Shorter median time to first response was noted in 1.5%ruxolitinib cream BID and QD treatment groups (8 and 12.5 days,respectively) versus vehicle (response not reached).

Similarly, among patients eligible for MCID analysis (baseline itch NRSof ≥2; n=272), higher rates of MCID were observed as early as Day 2(within 36 hours of treatment initiation) with 1.5% ruxolitinib creamBID (42.5%; P<0.01) and QD (37.2%; P<0.05) versus vehicle (13.6%);significantly higher rates of MCID were also observed for 1.5%ruxolitinib cream BID compared with triamcinolone at Day 2 (20.5%;P<0.05).

Strikingly, reductions in itch with ruxolitinib cream in the studyappeared greater via indirect comparison than reported improvement inpatients treated with dupilumab in phase 3 trials for patients withmoderate-to-severe AD, although baseline itch NRS scores were slightlyhigher in dupilumab studies (Simpson E L, et al. “Two phase 3 trials ofdupilumab versus placebo in atopic dermatitis,” N Engl J Med 2016;375:2335-48).

Itch NRS scores and Skindex-16 scores were correlated at baseline.Reduction in itch was positively associated with decreased QoL burden(Pearson correlation, 0.67; P<0.001).

TABLE 8 Change in Mean itch mean itch NRS score NRS score (vehicle armMean itch from transitioned NRS score baseline to 1.5% (1.5% (1.5% Meanitch ruxolitinib Time ruxolitinib ruxolitinib NRS score cream at Pointcream BID) cream BID) (vehicle) week 8) Baseline 5.9 5.7 —  2 Weeks 2.3−3.6 4.9 —  4 Weeks 2.1 −3.8 4.7 —  8 Weeks 1.8 −4.1 4.5 — 10 Weeks 1.9−4 — 2.3 12 Weeks 1.3 −4.6 — 2.4

Significant improvements in QoL were noted for all ruxolitinib creamregimens. The improvements were treatment regimen-dependent (FIG. 10 ).Mean percentage improvement from baseline in Skindex-16 overall scoresin patients treated with 1.5% ruxolitinib cream BID was 63.5% at Week 2(vehicle, 10.5%; P<0.001) and 73.2% at Week 8 (vehicle, 19.7%; P<0.001).At Week 4, the mean percentage improvement in overall score wassignificantly greater with 1.5% ruxolitinib cream BID (73.7%; P=0.02)compared with triamcinolone (59.7%). Itch NRS scores and Skindex-16scores were correlated at baseline. Reduction in itch was positivelyassociated with decreased QoL burden (Pearson correlation, 0.67;P<0.001).

As shown in Table 9 (double blind period), ruxolitinib cream was welltolerated and no associated with clinically significant site reactioneither in double-blind and open-label periods. There were no serioustreatment emergent adverse events (TEAEs) or discontinuations due toTEAEs during the open-label period. All treatment-related adverse eventswere mild or moderate in severity.

TABLE 9 Safety in the Open-Label Period by Initial Treatment GroupVehicle 0.1% TAC 0.15% RUX 0.5% RUX 1.5% RUX 1.5% RUX BID BID QD QD QDBID (n = 41) (n = 40) (n = 45) (n = 41) (n = 42) (n = 43) Days in study,28.0 28.0 28.0 28.0 28.0 28.0 median (range) (0-66.0) (12-38.0)(10.0-51.0) (13.0-40.0) (20.0-36.0) (50.0-106.0) Patients with TEAE, 5(12.2) 11 (27.5) 11 (24.2) 8 (19.5) 11 (26.2) 17 (39.5) n (%) Mostcommon TEAEs* Nasopharyngitis 1 (2.4) 1 (2.5) 4 (8.9) 1 (2.4) 2 (4.8) 4(9.3) Upper respiratory 1 (2.4) 2 (5.0) 0 1 (2.4) 2 (4.8) 1 (2.3) tractinfection AD 1 (2.4) 1 (2.5) 0 0 1 (2.4) 1 (2.3) Headache 0 0 1 (2.2) 1(2.4) 0 2 (4.7) Treatment- 0 0 0 1 (2.4) 1 (2.4) 2 (4.7) relatedTEAE, n(%) TEAE, treatment emergent adverse event. *Occurring in >1% of thetotal patient population.

In summary, ruxolitinib cream demonstrated improvement in EASI score,IGA response, and itch NRS score in a dose- and time-dependent manner.Responses to 1.5% ruxolitinib cream BID in the double-blind period weresustained in the open-label period (at Week 12: mean 84.9% improvementfrom baseline in EASI score; 58.5% IGA responders). Patients who crossedover to 1.5% ruxolitinib cream BID in the open-label period experiencedsubstantial improvements. The 1.5% ruxolitinib cream BID regimen broughtabout a prompt and sustained relief in itch that was significantlygreater than that of triamcinolone at Week 4. Finally, ruxolitinib creamwas well tolerated with no serious TEAEs related to the study drug andno patients discontinued because of TEAEs.

Example 3. Two Phase 3, Double-Blind, Randomized, 8-Week,Vehicle-Controlled Efficacy and Safety Studies of Ruxolitinib CreamFollowed by a Long-Term Safety Extension Period in Adolescents andAdults with Atopic Dermatitis

Two randomized, vehicle-control (VC) study were conducted in adolescentand adult (≥12 years old) participants with AD eligible for topicaltherapy. Approximately 600 participants were randomized in each study2:2:1 to ruxolitinib 0.75% cream BID, ruxolitinib 1.5% cream BID, orvehicle cream. In addition, approximately 20% of the overall studypopulation consisted of adolescents. Participants with baseline IGAscore of 2 constituted approximately 25% of the overall studypopulation. Participants with AD involvement of 3% to 20% BSA and IGAscore of 2 to 3 received blinded study treatment for 8 weeks.

The ruxolitinib in the creams is present as ruxolitinib phosphate andthe percentages are % (w/w) on a free base basis. The ruxolitinib creamformulations were oil-in-water cream formulations prepared as describedin Example 1 (see Table 5 of U.S. Patent Publ. No. 2015/0250790; the0.75% ruxolitinib cream was made by the method in Example 1 by adjustingfor the mass of the API in the formulation with water), which isincorporated herein by reference in its entirety.

For participants who met all study inclusion criteria and none of theexclusion criteria, study drug assignment was obtained. Key entrycriteria for participants to be eligible for the 8-week VC treatmentperiod was a diagnosis of AD (as defined by the Hanifin and Rajkacriteria) with a duration of disease for at least 2 years, IGA score of2 to 3, and a % BSA involvement of 3% to 20% (excluding scalp) atscreening and baseline.

Participants who developed additional areas of AD were allowed to treatthese additional areas with approval by the investigator as long as thetotal treated BSA did not exceed 20%, and there were no safety concernsregarding the additional application of study drug. Approval to treatadditional areas was to occur via telephone during the VC period,although the investigator, at his/her discretion, could ask theparticipant to return for an unscheduled visit. Through Week 8,participants continued to treat areas identified for treatment atbaseline even if the areas began to improve.

At Week 8, the study's primary endpoint, participants were assessed forefficacy with a percentage of participants achieving a treatmentresponse in IGA score. Participants were also assessed for safety andtolerability by monitoring the frequency, duration, and severity of AEs;performing physical examinations; and collecting vital signs andclinical/laboratory assessments at various timepoints during the study.

Participants who completed Week 8 assessments with no additional safetyconcerns will be offered to continue into the long-term safety (LTS)period with the same treatment regimen, except for those initially onvehicle, who will be equally assigned at Week 8 to 1 of the 2 activetreatment groups. At that time, the IGA score required for theparticipants to enter the LTS period is 0 to 4. With regard to % BSA,there is no required lower limit; participants may have BSA in the rangeof 0% to 20%.

In the LTS period, participants will have study visits every 4 weeksuntil the end of the study (52 weeks total). At those visits, AD lesionswill be evaluated by the investigator to confirm if the participantstill requires continuation of therapy (IGA≥1) or can otherwise(re)enter the observation/no treatment cycle (IGA=0).

During the LTS period (i.e., after the Week 8 visit), participants willself-evaluate recurrence of AD and will treat areas of the skin withactive AD changes (not to exceed 20% BSA). If lesions clear betweenstudy visits, participants will stop treatment applications 3 days afterthey have disappeared. Participants will restart treatment of their ADat the first sign of recurrence. In the event that new lesions areoutside of the usual location and/or are more wide spread than atbaseline, the participant is required to contact the site for approval.

Participants will be on study for a duration of up to 60 weeks (28 daysscreening, 8 weeks of treatment in the VC period, 44 weeks of treatmentin the LTS period, and a 30 (+7)-day safety follow-up.

The primary endpoint of the study was the proportion of patientsachieving IGA-TS at Week 8. The key secondary endpoints of the studywere: (i) the proportion of participants who achieve EASI-75 at Week 8;(ii) the proportion of participants with a ≥4 point improvement in itchNRS score from baseline at Week 8; and (iii) the proportion ofparticipants with a clinically meaningful improvement in the PROMISShort Form—Sleep Disturbance (8b) 24-hour recall score at Week 8.

Other secondary endpoints included: (i) the frequency, duration, andseverity of adverse events; performing physical examinations; collectingvital signs; and collecting laboratory data for hematology, serumchemistry, and urinalysis; (ii) proportion of participants achieving anIGA-TS at Weeks 2 and 4; (iii) proportion of participants achieving anIGA of 0 or 1 at each visit; (iv) proportion of participants with a ≥4point improvement in Itch NRS score from baseline to Weeks 2 and 4; (v)proportion of participants who achieve EASI50 at each visit during theVC period; (vi) proportion of participants who achieve EASI75 at Weeks 2and 4; (vii) proportion of participants who achieve EASI90 at each visitduring the VC period; (viii) mean percentage change from baseline inEASI score at each visit during the VC period; (ix) mean percentagechange from baseline in SCORAD score at each visit during the VC period;(x) change from baseline in Itch NRS score at each visit during the VCperiod; (xi) time to achieve Itch NRS score improvement of at least 2,3, or 4 points; (xii) change from baseline in Skin Pain NRS score ateach visit during the VC period; (xiii) proportion of participants witha clinically meaningful improvement in the PROMIS ShortForm—Sleep-Related Impairment (8a) 24-hour recall score at Weeks 2, 4,and 8; (xiv) change from baseline in PROMIS Short Form—Sleep RelatedImpairment (8a) 24-hour recall and Short Form—Sleep Disturbance (8b)24-hour recall score at Weeks 2, 4, and 8; (xv) PROMIS ShortForm—Sleep-Related Impairment (8a) 7 day recall and Short Form—SleepDisturbance (8b) 7 day recall score at Weeks 8, 12, 24, and 52; (xvi)change from baseline in AD afflicted % BSA at every visit; (xvii) changefrom baseline in POEM score at each visit; (xviii) change from baselinein DLQI score at Weeks 2, 4, 8, 12, 24, and 52 and at unscheduledvisits; (xix) mean PGIC score at Weeks 2, 4, and 8; (xx) proportion ofparticipants with each score on the PGIC at Weeks 2, 4, and 8; (xxi)proportion of participants with a score of either 1 or 2 on the PGIC atWeeks 2, 4, and 8; (xxii) change from baseline in EQ-5D-5L score duringthe VC period; (xxiii) change from baseline in WPAI-SHP v2.0 at Weeks 2,4, 8, 12, 24, 36, and 52; (xxiv) trough plasma concentrations ofruxolitinib at all study visits.

Subjects who met all of the following key inclusion criteria areeligible to be included in the study: (i) adolescents aged ≥12 to 17,inclusive, and men and women aged ≥18 years; (ii) diagnosed with AD asdefined by the Hanifin and Rajka criteria; (iii) history of AD for atleast 2 years; (iv) for the vehicle-control period, an IGA score of 2 to3 at screening and baseline; for the long-term safety period, an IGAscore of 0 to 4; (v) for the vehicle-control period, % BSA of ADinvolvement, excluding the scalp, of 3% to 20% at screening andbaseline; for the long-term safety period, % BSA of AD involvement,excluding scalp, of 0% to 20%; (vi) agreement to discontinue all agentsused to treat AD from screening through the final follow up visit; (vi)having at least 1 target lesion (which is representative of theparticipant's disease state and not present on the hands, feet orgenitalia) that measures about 10 cm² or more at screening and baseline;(vii) willingness to avoid pregnancy or fathering of children based onspecified criteria; and (viii) ability to comprehend and willingness tosign informed consent form or written informed consent from parent(s) orlegal guardian and written assent from participants when possible.

Subjects who met any of the following key exclusion criteria wereexcluded from the study: (i) Participants who have an unstable course ofAD (spontaneously improving or rapidly deteriorating) as determined bythe investigator in the 4 weeks prior to baseline; (ii) Participantswith concurrent conditions and history of other diseases: (a)Immunocompromised (e.g., lymphoma, acquired immunodeficiency syndrome,Wiskott-Aldrich syndrome); (b) chronic or acute infection requiringtreatment with systemic antibiotics, antivirals, antiparasitics,antiprotozoals, or antifungals within 2 weeks before baseline; (c)active acute bacterial, fungal, or viral skin infection (e.g., herpessimplex, herpes zoster, chicken pox) within 1 week before baseline; (d)any other concomitant skin disorder (e.g., generalized erythroderma suchas Netherton syndrome), pigmentation, or extensive scarring that, in theopinion of the investigator, may interfere with the evaluation of ADlesions or compromise participant safety; (e) presence of AD lesionsonly on the hands or feet without prior history of involvement of otherclassical areas of involvement such as the face or the folds; (f) othertypes of eczema; (iii) participants with any serious illness or medical,physical, or psychiatric condition(s) that, in the investigator'sopinion, would interfere with full participation in the study, includingadministration of study drug and attending required study visits; pose asignificant risk to the participant; or interfere with interpretation ofstudy data. For example: (a) clinically significant or uncontrolledcardiac disease, including unstable angina, acute myocardial infarctionwithin 6 months from Day 1 of study drug administration, New York HeartAssociation Class III or IV congestive heart failure, and arrhythmiarequiring therapy or uncontrolled hypertension (blood pressure >150/90mmHg) unless approved by medical monitor/sponsor; (b) participants witha history of malignancy in the 5 years preceding enrollment into thisstudy, except for adequately treated, nonmetastatic malignancies; (c)low hemoglobin (<10 g/dL); (d) severe renal disease on dialysis (serumcreatinine >2 mg/dL); (e) current and/or liver disease history,including known hepatitis B or C, with hepatic or biliary abnormalities;(iv) participants using any of the following treatments within theindicated washout period before baseline: (a) 5 half-lives or 12 weeks,whichever is longer—biologic agents (e.g., dupilumab); (b) 4weeks—systemic corticosteroids or adrenocorticotropic hormone analogs,cyclosporin, methotrexate, azathioprine, or other systemicimmunosuppressive or immunomodulating agents (e.g., mycophenolate ortacrolimus); (c) 2 weeks—immunizations and sedating antihistamines,unless on long-term stable regimen (nonsedating antihistamines arepermitted); (d) 1 week—use of other topical treatments for AD (otherthan bland emollients), such as corticosteroids, calcineurin inhibitors,coal tar (shampoo), antibiotics, antibacterial cleansing body wash/soap.Diluted sodium hypochlorite “bleach” baths are allowed as long as theydo not exceed 2 baths per week and their frequency remains the samethroughout the study; (v) participants who have previously received JAKinhibitors, systemic or topical; (vi) ultraviolet light therapy orprolonged exposure to natural or artificial sources of UV radiation(e.g., sunlight or tanning booth) within 2 weeks prior to baselineand/or intention to have such exposure during the study, which isthought by the investigator to potentially impact the participant's AD;(vii) positive serology test results at screening for HIV antibody;(viii) liver function tests: AST or ALT≥2×ULN; alkaline phosphataseand/or bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is acceptable ifbilirubin is fractionated and direct bilirubin <35%); (ix) pregnant orlactating participants, or those considering pregnancy; (x) history ofalcoholism or drug addiction within 1 year before screening or currentalcohol or drug use that, in the opinion of the investigator, willinterfere with the participant's ability to comply with theadministration schedule and study assessments; (xi) current treatment ortreatment within 30 days or 5 half-lives (whichever is longer) beforebaseline with another investigational medication or current enrollmentin another investigational drug protocol; (xii) participants who, in theopinion of the investigator, are unable or unlikely to comply with theadministration schedule and study evaluations; (xiii) participants whoare committed to a mental health institution by virtue of an orderissued either by the judicial or the administrative authorities; (xiv)employees of the sponsor or investigator or are otherwise dependents ofthem.

SCORAD is a tool to assess the extent and severity (i.e., intensity) ofeczema and will be completed before, during, and after treatment hasbegun to determine whether the treatment has been effective (Oakley,2009. https://www.dermnetnz.org/topics/scorad/. Accessed Nov. 1, 2018.).This was be performed during all VC study visits, starting at baseline.To determine extent, the rule of 9 or handprint method was used tocalculate the eczema affected area (A) as a percentage of the wholebody. Scores were added up to give a possible maximum of 100%. Todetermine intensity, a representative area of eczema was selected (seebelow for target lesion). The intensity of each of the following signsof redness, swelling, oozing/crusting, scratch marks, skin thickening(lichenification), dryness (this is assessed in an area where there isno inflammation) was assessed as follows: None (0); Mild (1); Moderate(2); Severe (3). Intensity scores are added together to give “B”(maximum score of 18). Subjective symptoms, that is, itch andsleeplessness, are scored by the participant using a visual analoguescale where “0” is no itch (or no sleeplessness) and “10” is the worstimaginable itch (or sleeplessness). These scores were added to give “C”(maximum score of 20). Total score gave approximate weights of 60% tointensity and 20% each to extent and subjective signs (i.e., insomnia,etc.) for the participant and were calculated as follows: A/5+7B/2+C.

Target lesion assessment was performed as follows. At baseline, a lesionthat is representative of the participant's overall disease and is to betreated with study drug was selected as the target lesion. This lesionwas identified, measured, and documented in the participant's medicalrecord at each subsequent visit during the VC period. A note should bemade in their medical record, and baseline photographs could be markedwith the location of the target lesion. The target lesion should nothave been on the hands, feet, or genitalia. The target lesion shouldhave had an area of approximately 10 cm² or more in size. The longestdiameter and the measurement perpendicular to the longest diameter weremeasured in millimeters. The skin stripping (with tape discs), lesionalskin S. aureus swabs, and TEWL assessments were taken from the targetlesion after photographs are taken and before study treatment wasapplied.

Total % BSA afflicted by AD was estimated at each visit in the VCperiod. Body surface area assessment was approximated to the nearest0.1% using the Palmar Method as guides, the palm plus 5 digits, withfingers tucked together and thumb tucked to the side (handprint), as 1%BSA and the thumb as 0.1% BSA.

Various patient-reported outcomes were assessed, including quality oflife (QoL) using the following tools: DQLI (Dermatology Life QualityIndex), PGIC (Patient Global Impression of Change), POEM(Patient-Oriented Eczema Measure), EQ-5D-5L (EQ-5D is a validated,self-administered, generic, utility questionnaire wherein participantswill rate their current health state based on the following criteria:mobility, self-care, usual activities, pain/discomfort, andanxiety/depression), WPAI:SHP (Work Productivity and Activity ImpairmentQuestionnaire: Specific Health Problem Version 2.0), Itch NRS, Skin PainNRS (Skin Pain Numerical Rating Scale), PROMIS Short Form—Sleep-RelatedImpairment (8a), and PROMIS Short Form—Sleep Disturbance (8b). In orderto avoid bias in the participants' responses to the questionnaires, allthese assessments were completed before any other evaluations or studyprocedures on the day of the study visit and prior to discussions withthe investigator or study site staff. At the baseline visit, allpatient-reported outcomes were completed before the participant's firststudy drug application.

Participants were issued a paper questionnaire or hand-held device(eDiary) for daily assessments. The participant was instructed tocomplete the diary during specific timepoints needed for each assessmentbeginning on the day of screening through Week 8 or treatmentdiscontinuation. Daily assessments was performed by participants via adiary starting at the screening visit and all visits during the VCperiod: The participant rated (during the past 24 hours) the following:Itch NRS—the worst level of itch will be recorded in the evening; SkinPain NRS—the worst level of pain will be recorded in the evening; PROMISquestionnaires; Short Form—Sleep-Related Impairment (8a) will becompleted in the evening; Short Form—Sleep-Disturbance (8b) will beassessed in the morning.

During all VC site visits, the following was assessed: EQ-5D-5L—startsat screening; WPAI:SHP—starts at screening; DLQI/CDLQI—starts at Day 1;POEM—starts at Day 1; PGIC—starts at Week 2.

-   -   During the LTS period, the following will be assessed: EQ-5D-5L;        WPAI:SHP;    -   DLQI/CDLQI; POEM; PROMIS Short Form—Sleep-Related Impairment        (8a) and Short Form—Sleep-Disturbance (8b):

The DLQI is a simple, 10-question validated questionnaire to measure howmuch the skin problem has affected the participant over the previous 7days as outlined in the SoAs (Finlay A Y, Khan G K, “Dermatology LifeQuality Index (DLQI)—a simple practical measure for routine clinicaluse,” Clin Exp Dermatol 1994; 19:210-216.). The participant, aged ≥16years and over, answered the questionnaire with either (1) very much,(2) a lot, (3) a little, or (4) not at all. The questionnaire wasanalyzed under 6 headings as follows: Symptoms and feelings (Questions 1and 2); Daily activities (Questions 3 and 4); Leisure (Questions 5 and6); Work and school (Question 7); Personal relations (Questions 8 and9); Treatment (Question 10).

CDLQI is the youth/children's version of the DLQI and was completed byadolescents aged ≥12 years to <16 years. It is self-explanatory andcould be simply given to the participant who was asked to fill it in andwho could ask the help of the parent or guardian. The questionnaire wasanalyzed under 6 headings as follows: Symptoms and feelings (Questions 1and 2); Leisure (Questions 4, 5, and 6); School or holidays (Question7); Personal relationships (Questions 3 and 8); Sleep (Question 9);Treatment (Question 10); Patient Global Impression of Change

The PGIC is a participants' self-reporting measure that reflects theirbelief about the efficacy of treatment. The PGIC is a 7-point scaledepicting a participant's rating of overall improvement and will becaptured during site visits during the VC period (Hurst H, Bolton J.“Assessing the clinical significance of change scores recorded onsubjective outcome measures,” J Manipulative Physiol Ther 2004;27:26-35). The participant will answer the following: “Since the startof the treatment you've received in this study, your atopic dermatitisin areas treated with the study drug is: (1) very much improved, (2)much improved, (3) minimally improved, (4) no change, (5) minimallyworse, (6) much worse, and (7) very much worse.”

The POEM is a 7-question quality-of-life assessment that asks how manydays the participant has been bothered by various aspects of their skincondition during the past 7 days obtained as outlined in the SoAs(Charman C R, et al., Arch Dermatol 2004, 140:1513-1519).

The EQ-5D-5L: The EQ-5D is a validated, self-administered, genericutility questionnaire wherein participants (adolescents and adults) ratetheir current health state based on the following criteria (dimensions):mobility, self-care, usual activities, pain/discomfort, andanxiety/depression. The 5L indicates that for each dimension, there are5 levels, which are as follows: no problems, slight problems, moderateproblems, severe problems, and extreme problems. During all VC periodstudy visits (starting at screening) and at specific LTS visits (Weeks12, 24, 36, 52, and follow-up visit), the participant was asked toindicate his/her health state over the past 7 days, by ticking the boxnext to the most appropriate statement in each of the 5 dimensions. Thedigits for the 5 dimensions can be combined into a 5-digit number thatdescribes the participant's health state (EuroQol Research Foundation.EQ-5D-5L. 2017. https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/.Accessed Jul. 17, 2018).

The WPAI:SHP v2.0 questionnaire is a validated 6-item instrument,completed during all site visits starting at screening, during the VCperiod, and at specific LTS visits (Weeks 12, 24, 36, 52 and follow-upvisit) that measures the effect of overall health and specific symptomson productivity at work and regular activities outside of it during thepast 7 days (Reilly M C, Zbrozek A S, Dukes E M, “The validity andreproducibility of a work productivity and activity impairmentinstrument,” PharmacoEconomics 1993; 4:353-365).

The Itch NRS is a daily patient-reported measure (24-hour recall) of theworst level of itch intensity. Participants were asked to rate theitching severity because of their AD by selecting a number from 0 (noitch) to 10 (worst imaginable itch) that best describes their worstlevel of itching in the past 24 hours. Participants were issued a diaryin which to record itch severity. The participants was instructed tocomplete the diary each night beginning on the day of screening throughthe last application of study drug in the VC period.

The Skin Pain NRS is a daily patient-reported measure (24-hour recall)of the worst level of pain intensity from 0 (no pain) to 10 (worstimaginable pain). Participants were asked, “Rate the pain severity fromyour atopic dermatitis skin changes by selecting a number that bestdescribes your worst level of pain in the past 24 hours,” as outlined inthe SoA.

Participants were issued a diary in which to record skin pain severityeach evening, rating the worst pain in the past 24-hours. Theparticipants were instructed to complete the diary each night beginningon the day of screening through the last application of study drug inthe VC period.

PROMIS® (Patient-Reported Outcomes Measurement Information System) is aset of widely used and accepted patient-reported outcome measurementsthat have been developed with strong clinical outcome assessmentdevelopment methods and are psychometrically supported. The selectedPROMIS Short Form—Sleep-Related Impairment (8a) and ShortForm—Sleep-Disturbance (8b) questionnaires were modified to be completedwith a diary on a daily basis with a 24-hour recall: ShortForm—Sleep-Related Impairment (8a) is collected in the evening, andShort Form—Sleep-Disturbance (8b) is collected in the morning during theVC period. Starting at Week 8 and during the LTS period, these were/willbe done with a 7-day recall period and be completed at the site duringstudy visits.

The PROMIS Short Form—Sleep-Related Impairment (8a) questionnaire, wascompleted in the evening during the VC period. This assessment focuseson self-reported perceptions of alertness, sleepiness, and tirednessduring usual waking hours and the perceived functional impairmentsduring wakefulness associated with sleep problems or impaired alertness(Buysse, Sleep 2010; 33:781-792). The questionnaire has 8 simplequestions with a 5-point scale with a range in score from 8 to 40, withhigher scores indicating greater severity of sleep-related impairment.Each item asks the participant to rate the severity of the participant'ssleep impairment. The recall period was the past 24 hours for the VCperiod and the past 7 days for the LTS period.

The PROMIS Short Form—Sleep Disturbance (8b) questionnaire was completedin the morning during the VC period. This assessment is self-reportedperceptions of sleep quality, sleep depth, and restoration associatedwith sleep. Sleep disturbance does not focus on symptoms of specificsleep disorders and does not provide subjective estimates of sleepquantities (e.g., total amount of sleep, time to fall asleep, amount ofwakefulness during sleep; Buysse et al 2010). The sleep disturbanceshort form is generic rather than disease-specific. The questionnaire isalso 5-point scale with a range in score from 8 to 40, with higherscores indicating greater severity of sleep disturbance. Each item askedthe participant to rate the severity of the participant's sleepdisturbance. The recall period was the past 24 hours for the VC periodand the past 7 days for the LTS period.

Results from the VC Period

In TRuE-AD1 (Study 303), 631 patients were randomized (vehicle, n=126;0.75% BID, n=252; 1.5% BID, n=253); the median (range) age was 32.0(12-85) years and 62.0% of patients were female. Seventy-three patients(11.6%) discontinued from the study. In TRuE-AD2 (Study 304), 618patients were randomized (vehicle, n=124; 0.75% BID, n=248; 1.5% BID,n=246); the median (range) age was 33.0 (12-85) years and 61.5% werefemale. Fifty-seven patients (9.2%) discontinued from the study. Thefull demographics for TRuE-AD1 and TRuE-AD2 are shown in Tables 10 and11, respectively. Mean baseline itch NRS score for the pooled TRuE-AD1and TRuE-AD2 populations for vehicle, 0.75% BID, and 1.5% BIDpopulations were 5.15, 5.14, and 5.09, respectively.

TABLE 10 Parameters Total Parameters Total Age Race n(%) Mean (SD) 35.2(18.15) White 431 (68.3) Median (Min-Max) 32 (12-85) Black 140 (22.2)12-17 n(%) 123 (19.5) Asian 32 (5.1) >=18 n(%) 508 (80.5) Others 28(4.5) Sex n(%) Region n(%) Male 240 (38) North America 440 (69.7) Female391 (62) Europe 191 (30.3) Baseline IGA n(%) Baseline EASI n(%) 2 152(24.1) <=7 318 (50.4) 3 479 (75.9) >7 313 (49.6)

TABLE 11 Parameters Total Parameters Total Age Race n(%) Mean (SD) 36.4(18.38) White 436 (70.6) Median (Min-Max) 33 (12-85) Black 152 (24.6)12-17 n(%) 122 (19.7) Asian 14 (2.3) >=18 n(%) 496 (80.3) Others 16(2.6) Sex n(%) Region n(%) Male 238 (38.5) North America 415 (67.2)Female 380 (61.5) Europe 203 (32.8) Baseline IGA n(%) Baseline EASI n(%)2 160 (25.9) <=7 302 (48.9) 3 458 (74.1) >7 316 (51.1)

The efficacy population consisted of 631 patients for TRuE-AD1 (allrandomized patients), and 577 patients for TRuE-AD2 (vehicle, n=118;0.75% BID, n=231; 1.5% BID, n=228). All patients who received ≥1 dose oftreatment (all randomized patients) were included in the safetypopulation in both studies.

A summary of the primary and major secondary efficacy endpoints forTRuE-AD1 (Study 303) and TRuE-AD2 (Study 304) are shown in Tables 12 and13.

TABLE 12 Vehicle 0.75% BID 1.5% BID N 126 252 253 IGA-TS 15.1% 50% **53.8% ** EASI75 24.6% 56.0% ** 62.1% ** ITCH4 15.4% 40.4% ** 52.2%**{circumflex over ( )} PROMIS6 8b  9.5% 21% * 22.3% * PROMIS6 8a 13.2%20.2% 21.6% ** p < 0.0001, Rux vs. vehicle; * p < 0.01 Rux vs. vehicle;{circumflex over ( )} p = 0.04, 1.5% BID vs 0.75% BID

TABLE 13 Vehicle 0.75% BID 1.5% BID N 118 231 228 IGA-TS 7.6% 39.0% **51.3% **{circumflex over ( )}{circumflex over ( )} EASI75 14.4% 51.5% **61.8% **{circumflex over ( )} ITCH4 16.3% 42.7% ** 50.7% ** PROMIS6 8b19.1% 20.7% 25.6% PROMIS6 8a 13.5% 20.0% 23.1% ** p < 0.0001, Rux vs.vehicle; * p < 0.01 Rux vs. vehicle; {circumflex over ( )} p = 0.04,1.5% BID vs 0.75% BID

In TRuE-AD1 and TRuE-AD2, respectively, significantly more patientstreated with ruxolitinib cream achieved IGA treatment success (0.75%BID, 50.0% and 39.0%; 1.5% BID, 53.8% and 51.3%) vs vehicle (15.1% and7.6%; all P<0.0001) (FIG. 11 ).

EASI-75 was achieved by 56.0% and 51.5% of patients applying ruxolitinibcream 0.75% BID, as well as 62.1% and 61.8% on 1.5% BID vs 24.6% and14.4% on vehicle (all P<0.0001) in TRuE-AD1 and TRuE-AD2, respectively(FIG. 12 ). In TRuE-AD1 (Study 303), Eczema Area and Severity Indexscores decreased over time with clear separation for both activetreatment groups from the vehicle treatment group by Week 2. In thepooled TRuE-AD1 (Study 303) and TRuE-AD2 (Study 304) studies, EczemaArea and Severity Index scores decreased over time with clear separationfor both active treatment groups from the vehicle treatment group byWeek 2 (see FIGS. 31, 32, and 33 ).

In both studies, patients who applied ruxolitinib cream (0.75% BID or1.5% BID) achieved statistically significant itch reductions (NRS4)compared with vehicle at Week 8 (FIG. 13 ; numbers are for patients withbaseline itch NRS score ≥4). In addition to attaining sustained itchreduction at Week 8, patients who applied ruxolitinib cream (0.75% BIDor 1.5% BID) also experienced rapid reduction in itch within 1-2 days(FIG. 14 and FIG. 15 ; Table 14 (TRuE-AD1; mean baseline itch NRS score6.39, 6.44, and 6.45 for vehicle, 0.75% BID, and 1.5% BID,respectively); Table 15 (TRuE-AD2; mean baseline itch NRS score 6.42,6.38, and 6.38 for vehicle, 0.75% BID, and 1.5% BID, respectively);numbers are for patients with baseline itch NRS score ≥4).

TABLE 14 Mean change from baseline itch NRS score Day Vehicle 0.75% BIDp-value 1.5% BID p-value N 78 156 161 1 −0.21 −0.61 −0.60 2 −0.11 −1.43<0.0001 −1.66 <0.0001 3 −0.46 −1.81 <0.0001 −2.05 <0.0001 4 −0.38 −2.21<0.0001 −2.45 <0.0001 5 −0.5 −2.14 <0.0001 −2.66 <0.0001 6 −0.88 −2.20<0.0001 −2.79 <0.0001 7 −0.88 −2.33 <0.0001 −2.88 <0.0001 14 −1.32 −3.12<0.0001 −3.66 <0.0001 21 −1.40 −3.38 <0.0001 −4.06 <0.0001 28 −1.49−3.47 <0.0001 −4.46 <0.0001 35 −1.91 −3.65 <0.0001 −4.73 <0.0001 42−1.83 −3.51 <0.0001 −4.52 <0.0001 49 −2.22 −3.65 <0.0001 −4.80 <0.000156 −2.16 −3.52 <0.0001 −4.64 <0.0001 *p-value between the ruxolitinibcream group and vehicle

TABLE 15 Mean change from baseline itch NRS score Day Vehicle 0.75% BIDp-value 1.5% BID p-value N 80 157 146 1 −0.10 −0.48 0.0598 −0.60 0.01592 −0.10 −1.29 <0.0001 −1.42 <0.0001 3 −0.22 −1.67 <0.0001 −1.82 <0.00014 −0.03 −1.90 <0.0001 −2.23 <0.0001 5 −0.33 −1.99 <0.0001 −2.25 <0.00016 −0.23 −2.30 <0.0001 −2.27 <0.0001 7 −0.26 −2.41 <0.0001 −2.51 <0.000114 −1.22 −3.02 <0.0001 −3.36 <0.0001 21 −1.24 −3.43 <0.0001 −3.65<0.0001 28 −1.53 −3.52 <0.0001 −3.61 <0.0001 35 −1.59 −3.94 <0.0001−3.80 <0.0001 42 −1.59 −3.95 <0.0001 −3.87 <0.0001 49 −1.70 −3.94<0.0001 −3.82 <0.0001 56 −1.77 −3.88 <0.0001 −3.89 <0.0001 * p-valuebetween the ruxolitinib cream group and vehicle

In both TRuE-AD1 and TRuE-AD2, significantly greater itch reduction ascompared to vehicle was observed by day 2 (within 12 hours of firstapplication of ruxolitinib cream) for patients receiving 1.5%ruxolitinib cream BID (Tables 16 (TRuE-AD1) and Table 17 (TRuE-AD2), asmeasured for the entire patient population). Mean baseline itch NRSscore for vehicle, 0.75% BID, and 1.5% BID for Table 16 was 5.06, 5.13,and 5.15, respectively. Mean baseline itch NRS score for vehicle, 0.75%BID, and 1.5% BID for Table 17 was 5.25, 5.15, and 5.02, respectively.By day 2 (within 36 hours of the first application of ruxolitinibcream), patients achieved significantly greater itch reduction for 0.75%BID ruxolitinib cream in both studies.

TABLE 16 Mean change from baseline itch NRS score Day Vehicle 0.75% BIDp-value 1.5% BID p-value N 126 252 253 1 −0.09 −0.41 0.0512 −0.48 0.01612 −0.03 −1.12 <0.0001 −1.27 <0.0001 3 −0.09 −1.49 <0.0001 −1.61 <0.00014 0.06 −1.33 <0.0001 −1.90 <0.0001 5 −0.16 −1.78 <0.0001 −2.07 <0.0001 6−0.45 −1.81 <0.0001 −2.18 <0.0001 7 −0.43 −1.93 <0.0001 −2.23 <0.0001 14−0.78 −2.60 <0.0001 −2.81 <0.0001 21 −0.98 −2.72 <0.0001 −3.08 <0.000128 −1.03 −2.81 <0.0001 −3.39 <0.0001 35 −1.32 −2.99 <0.0001 −3.69<0.0001 42 −1.24 −2.83 <0.0001 −3.44 <0.0001 49 −1.41 −2.98 <0.0001−3.65 <0.0001 56 −1.51 −2.97 <0.0001 −3.53 <0.0001 * p-value between theruxolitinib cream group and vehicle

TABLE 17 Mean change from baseline itch NRS score Day Vehicle 0.75% BIDp-value 1.5% BID p-value N 118 231 228 1 −0.12 −0.35 0.1713 −0.48 0.02902 −0.08 −1.12 <0.0001 −1.21 <0.0001 3 −0.20 −1.42 <0.0001 −1.45 <0.00014 −0.02 −1.60 <0.0001 −1.81 <0.0001 5 −0.24 −1.65 <0.0001 −1.84 <0.00016 −0.22 −1.94 <0.0001 −1.83 <0.0001 7 −0.24 −2.00 <0.0001 −2.07 <0.000114 −0.94 −2.52 <0.0001 −2.75 <0.0001 21 −1.00 −2.79 <0.0001 −2.95<0.0001 28 −1.09 −2.89 <0.0001 −2.88 <0.0001 35 −1.29 −3.15 <0.0001−3.10 <0.0001 42 −1.23 −3.21 <0.0001 −3.03 <0.0001 49 −1.40 −3.13<0.0001 −3.01 <0.0001 56 −1.33 −3.04 <0.0001 −3.17 <0.0001 *p-valuebetween the ruxolitinib cream group and vehicle

The pooled data for the TRuE-AD1 and TRuE-AD2 studies for mean changefrom baseline in daily itch NRS score is shown in Table 18 and in FIG.25 . The p-values show that the differences for 0.75% and 1.5%ruxolitinib cream become significant by day 1 (within 12 hours). Themean change from baseline in daily itch NRS score at day 1 (within 12hours) for 0.75% and 1.5% ruxolitinib cream is −0.38 and −0.48,respectively. The mean change from baseline in daily itch NRS score atday 2 (within 36 hours) for 0.75% and 1.5% ruxolitinib cream is −1.12and −1.24, respectively.

TABLE 18 Study Mean change from baseline in daily itch NRS score DayVehicle 0.75% BID p-value 1.5% BID p-value 1 −0.10 −0.38 0.0180 −0.480.0011 2 −0.06 −1.12 <0.0001 −1.24 <0.0001 3 −0.14 −1.45 <0.0001 −1.53<0.0001 4 0.02 −1.72 <0.0001 −1.86 <0.0001 5 −0.20 −1.72 <0.0001 −1.96<0.0001 6 −0.34 −1.87 <0.0001 −2.01 <0.0001 7 −0.34 −1.97 <0.0001 −2.15<0.0001 8 −0.53 −2.09 <0.0001 −2.30 <0.0001 9 −0.53 −2.13 <0.0001 −2.36<0.0001 10 −0.66 −2.19 <0.0001 −2.39 <0.0001 11 −0.67 −2.17 <0.0001−2.45 <0.0001 12 −0.75 −2.38 <0.0001 −2.59 <0.0001 13 −0.86 −2.46<0.0001 −2.67 <0.0001 14 −0.86 −2.56 <0.0001 −2.78 <0.0001 15 −0.91−2.54 <0.0001 −2.92 <0.0001 16 −1.00 −2.58 <0.0001 −2.97 <0.0001 17−0.96 −2.63 <0.0001 −2.93 <0.0001 18 −0.94 −2.68 <0.0001 −3.03 <0.000119 −1.04 −2.64 <0.0001 −3.09 <0.0001 20 −1.08 −2.66 <0.0001 −3.11<0.0001 21 −0.99 −2.75 <0.0001 −3.02 <0.0001 22 −1.09 −2.78 <0.0001−3.18 <0.0001 23 −0.97 −2.74 <0.0001 −3.05 <0.0001 24 −1.01 −2.78<0.0001 −3.05 <0.0001 25 −1.05 −2.78 <0.0001 −3.17 <0.0001 26 −0.95−2.79 <0.0001 −3.11 <0.0001 27 −1.06 −2.75 <0.0001 −3.06 <0.0001 28−1.06 −2.85 <0.0001 −3.16 <0.0001

In patients having baseline itch NRS score of ≥2, the number ofresponders reaching a ≥2-point improvement in itch NRS score becamestatistically significant by day 2 (within 36 hours of the firstapplication of ruxolitinib cream) for patients receiving 0.75% and 1.5%BID ruxolitinib cream (Table 19 (TRuE-AD1) and Table 20 (TRuE-AD2).

TABLE 19 Participants achieving a ≥2-point reduction in itch NRS score-Number of responders out of total (%) Day Vehicle 0.75% BID p-value 1.5%BID p-value 1 9 of 96 31 of 201 0.2030 28 of 207 0.4099 (9.4%) (15.4%)(13.5%) 2 8 of 95 64 of 197 <0.0001 78 of 199 <0.0001 (8.4%) (32.5%)(39.2%) 3 16 of 97 72 of 195 0.0003 91 of 199 <0.0001 (16.5%) (36.9%)(45.7%) 4 13 of 95 96 of 199 <0.0001 105 of 198 <0.0001 (13.7%) (48.2%)(53.0%) 5 12 of 94 92 of 193 <0.0001 115 of 198 <0.0001 (12.8%) (47.7%)(58.1%) 6 22 of 92 99 of 192 <0.0001 121 of 203 <0.0001 (23.9%) (51.6%)(59.6%) 7 19 of 93 101 of 194 <0.0001 116 of 203 <0.0001 (20.4%) (52.1%)(57.4%) 8 20 of 91 108 of 194 <0.0001 116 of 200 <0.0001 (22.0%) (55.7%)(58.0%) 9 23 of 91 115 of 188 <0.0001 115 of 197 <0.0001 (25.3%) (61.2%)(58.4%) 10 23 of 90 110 of 188 <0.0001 123 of 191 <0.0001 (25.6%)(58.5%) (64.4%) 11 24 of 87 110 of 179 <0.0001 121 of 187 <0.0001(27.6%) (61.5%) (64.7%) 12 24 of 89 121 of 188 <0.0001 119 of 184<0.0001 (27.0%) (64.4%) (64.7%) 13 28 of 91 119 of 193 <0.0001 129 of193 <0.0001 (30.8%) (61.7%) (66.8%) 14 26 of 92 124 of 189 <0.0001 134of 196 <0.0001 (28.3%) (65.6%) (68.4%)

TABLE 20 Participants achieving a ≥2-point reduction in itch NRS score-Number of responders out of total (%) Day Vehicle 0.75% BID p-value 1.5%BID p-value 1 4 of 92 30 of 174 0.0032 22 of 175 0.0447 (4.3%) (17.2%)(12%) 2 7 of 91 51 of 180 <0.0001 51 of 172 <0.0001 (7.7%) (28.3%)(29.7%) 3 12 of 88 59 of 174 0.0004 64 of 170 <0.0001 (13.6%) (33.9%)(37.6%) 4 10 of 88 59 of 166 <0.0001 81 of 172 <0.0001 (11.4%) (35.5%)(47.1%) 5 12 of 89 76 of 172 <0.0001 80 of 170 <0.0001 (13.5%) (44.2%)(47.1%) 6 10 of 87 81 of 167 <0.0001 82 of 170 <0.0001 (11.5%) (48.5%)(48.2%) 7 13 of 92 89 of 172 <0.0001 94 of 175 <0.0001 (14.1%) (51.7%)(53.7%) 8 13 of 90 96 of 174 <0.0001 97 of 171 <0.0001 (14.4%) (55.2%)(56.7%) 9 13 of 84 94 of 170 <0.0001 88 of 165 <0.0001 (15.5%) (55.3%)(53.3%) 10 18 of 90 93 of 166 <0.0001 95 of 165 <0.0001 (20.0%) (56.0%)(57.6%) 11 17 of 87 94 of 174 <0.0001 94 of 167 <0.0001 (20.2%) (54.0%)(56.3%) 12 21 of 90 100 of 172 <0.0001 104 of 164 <0.0001 (23.3%)(58.1%) (63.4%) 13 20 of 86 100 of 167 <0.0001 102 of 166 <0.0001(23.3%) (59.9%) (61.4%) 14 24 of 88 105 of 170 <0.0001 107 of 170<0.0001 (27.3%) (61.8%) (62.9%)

In patients having baseline itch NRS score of ≥2, the number ofresponders reaching a ≥2-point improvement in itch NRS score becamestatistically significant by day 2 (within 36 hours of the firstapplication of ruxolitinib cream) for patients receiving 0.75% and 1.5%BID ruxolitinib cream (Table 21 (TRuE-AD land TRuE-AD2)). The differencebetween 0.75% and 1.5% ruxolitinib cream versus vehicle becamestatistically significant at day 1 (within 12 hours).

TABLE 21 Participants achieving a ≥2-point reduction in itch NRSscore-Number of responders out of total (%) Day Vehicle 0.75% BIDp-value 1.5% BID p-value 1 13 of 188 61 of 375 0.0021 50 of 382 0.0300(0.7%) (2.7%) (3.1%) 2 15 of 186 115 of 377 <0.0001 129 of 371 <0.0001(8.1%) (30.5%) (34.8%) 3 28 of 185 131 of 369 <0.0001 155 of 369 <0.0001(15.1%) (35.5%) (42.0%) 4 23 of 183 155 of 365 <0.0001 186 of 370<0.0001 (12.6%) (42.5%) (50.3%) 5 24 of 183 168 of 365 <0.0001 195 of368 <0.0001 (13.1%) (46.0%) (53.0%) 6 32 of 179 180 of 359 <0.0001 203of 373 <0.0001 (17.9%) (50.1%) (54.4%) 7 32 of 185 190 of 366 <0.0001210 of 377 <0.0001 (17.3%) (51.9%) (55.7%)

In patients having baseline itch NRS score of ≥4, the number ofresponders reaching a ≥4-point improvement in itch NRS score becamestatistically significant by day 4 of the first application ofruxolitinib cream for patients receiving 0.75% BID ruxolitinib cream andby day 3 of the first application of ruxolitinib cream for patientsreceiving 1.5% BID ruxolitinib cream (Table 22 (TRuE-AD1 and TRuE-AD2and FIG. 26 )).

TABLE 22 Participants achieving a ≥4-point reduction in itch NRS score-Number of responders out of total (%) Day Vehicle 0.75% BID p-value 1.5%BID p-value 1 1 of 144 8 of 291 0.0807 9 of 288 0.1290 (0.7%) (2.7%)(3.1%) 2 3 of 145 26 of 293 0.0042 31 of 277 0.0012 (2.1%) (8.9%)(11.2%) 3 3 of 142 38 of 286 0.0002 44 of 276 <0.0001 (2.1%) (13.3%)(15.9%) 4 4 of 142 51 of 285 <0.0001 64 of 277 <0.0001 (2.8%) (17.9%)(23.1%) 5 5 of 141 55 of 285 <0.0001 67 of 275 <0.0001 (3.5%) (19.3%)(24.4%) 6 8 of 140 62 of 279 <0.0001 78 of 277 <0.0001 (5.7%) (22.2%)(28.2%) 7 10 of 142 68 of 281 <0.0001 86 of 283 <0.0001 (7.0%) (24.2%)(30.4%)

Patients achieve an IGA score of 0 or 1 by Week 2 for patients receiving0.75% and 1.5% BID ruxolitinib cream on TRuE-AD1 study (Table 23).Patients achieve an IGA score of 0 or 1 by Week 2 for patients receiving1.5% BID ruxolitinib cream and by Week 4 for patients receiving 0.75%BID ruxolitinib cream on TRuE-AD2 study (Table 24).

TABLE 23 Participants achieving achieve an IGA score of 0 or 1- Numberof responders out of total (%) Week Vehicle 0.75% BID p-value 1.5% BIDp-value 2 8 of 126 82 of 252 <0.0001 88 of 253 <0.0001 (6.3%) (32.5%)(34.8%) 4 19 of 126 134 of 252 <0.0001 139 of 253 <0.0001 (15.1%)(53.2%) (54.9%) 8 30 of 126 148 of 252 <0.0001 159 of 253 <0.0001(23.8%) (58.7%) (62.8%)

TABLE 24 Participants achieving achieve an IGA score of 0 or 1- Numberof responders out of total (%) Week Vehicle 0.75% BID p-value 1.5% BIDp-value 2 11 of 118 56 of 231 0.0008 79 of 228 <0.0001 (9.3%) (24.2%)(34.6%) 4 20 of 118 106 of 231 <0.0001 120 of 228 <0.0001 (16.9%)(45.9%) (52.6%) 8 19 of 118 118 of 231 <0.0001 142 of 228 <0.0001(16.1%) (51.1%) (62.3%)

Patients achieve EASI90 for patients receiving 0.75% and 1.5% BIDruxolitinib cream (Table 25 (TRuE-AD1) and Table 26 (TRuE-AD2). Thedifference between 0.75% and 1.5% ruxolitinib cream versus vehicle wasstatistically significant by week 2.

TABLE 25 Participants achieving achieve EASI90-Number of responders outof total (%) Week Vehicle 0.75% BID p-value 1.5% BID p-value 2 3 of 12632 of 252 0.0008 50 of 253 <0.0001 (2.4%) (12.7%) (19.8%) 4 5 of 126 77of 252 <0.0001 92 of 253 <0.0001 (4.0%) (30.6%) (36.4%) 8 12 of 126 96of 252 <0.0001 112 of 253 <0.0001 (9.5%) (38.1%) (44.3%)

TABLE 26 Participants achieving achieve EASI90-Number of responders outof total (%) Week Vehicle 0.75% BID p-value 1.5% BID p-value 2 1 of 11825 of 231 0.0004 36 of 228 <0.0001 (0.8%) (10.8%) (15.8%) 4 3 of 118 59of 231 <0.0001 74 of 228 <0.0001 (2.5%) (25.5%) (32.5%) 8 5 of 118 81 of231 <0.0001 99 of 228 <0.0001 (4.2%) (35.1%) (43.4%)

At Week 8, a ≥6-point improvement in the PROMIS sleep impairment score(8a) was reached by 21.0% and 20.7% of patients applying ruxolitinibcream 0.75% BID and 22.3% and 25.6% of patients applying ruxolitinibcream 1.5% BID for TRuE-AD1 and TRuE-AD2, respectively (FIG. 16 ). AtWeek 8, a ≥6-point improvement in the PROMIS sleep impairment score (8a)was reached by 20.1% of patients applying ruxolitinib cream 0.75% BIDand 22.3% of patients applying ruxolitinib cream 1.5% BID for the pooledTRuE-AD1 (Study 303) and TRuE-AD2 (FIG. 30 ). At Week 8, a ≥6-pointimprovement in the PROMIS sleep disturbance score (8a) was reached by20.2% and 20.0% of patients applying ruxolitinib cream 0.75% BID and21.6% and 23.1% of patients applying ruxolitinib cream 1.5% BID forTRuE-AD1 and TRuE-AD2, respectively (FIG. 17 ). At Week 8, a ≥6-pointimprovement in the PROMIS sleep disturbance score (8a) was reached by20.9% of patients applying ruxolitinib cream 0.75% BID and 23.8% ofpatients applying ruxolitinib cream 1.5% BID for the pooled TRuE-AD1(Study 303) and TRuE-AD2 (Study 304) (FIG. 29 ).

With respect to the 0.75% BID ruxolitinib cream, the patient responsesin IGA-TS and EASI75 were unexpectedly improved at weeks 2, 4, and 8,compared to the 1.5% QD ruxolitinib cream (from Phase 2) (see Tables 27and 28).

TABLE 27 Proportion of patient that achieve IGA-TS (%) Week 0.75% BID1.5% QD^(b) 1.5% BID^(a) 1.5% BID^(b) 2 30.6 13.5 25.0 8.0 4 38.9 21.246.9 38.0 8 50.0 30.8 59.4 48.0 ^(a)See FIG. 22 (Phase 3 results)^(b)See FIG. 4 (Phase 2 results)

TABLE 28 Proportion of patient that achieve EASI75 (%) Week 0.75%BID^(a) 1.5% QD^(b) 1.5% BID^(a) 1.5% BID^(b) 2 36.1 21.2 37.5 30.0 463.9 40.4 53.3 56.0 8 75.0 53.8 71.9 64.0 ^(a)See FIG. 23 (Phase 3results) ^(b)See FIG. 3 (Phase 2 results)

The overall rate of treatment-emergent adverse events in both studiesafter 8 weeks of treatment was comparable between the ruxolitinib creamregimens and vehicle (0.75% BID, 29.4%; 1.5% BID, 28.9%; vehicle, 34.9%in TRuE-AD1; and 0.75% BID, 29.4%; 1.5% BID, 23.6%; vehicle, 32.3% inTRuE-AD2). The rate of serious adverse events was comparable in alltreatment groups (0.75% BID, 0.8%; 1.5% BID, 0.6%; vehicle, 0.8%). Noclinically significant application site reactions were observed,including areas of sensitive skin. For example, application site burnoccurred at comparable or lower rates than for vehicle (0.75% BID, 0.0%;1.5% BID, 0.8%; vehicle, 1.6% in TRuE-AD1; and 0.75% BID, 0.8%; 1.5%BID, 0.8%; vehicle, 6.5% in TRuE-AD2). Application site pruritusoccurred at comparable or lower rates than for vehicle (0.75% BID, 1.2%;1.5% BID, 0.0%; vehicle, 1.6%). Changes in hemoglobin (g/L) andplatelets (10⁹/L) over 8 weeks were comparable between the treatmentgroups (0.75% BID and 1.5% BID) versus vehicle (FIG. 18-21 ).

Patients with More Severe Atopic Dermatitis with Higher Body SurfaceInvolvement

Strikingly, it was found that patients with more severe atopicdermatitis with higher body surface involvement appeared to respond wellto topical ruxolitinib cream in the TRuE-AD1 and TRuE-AD2 studies. Thesepatients generally have a Body Surface Area of atopic dermatitisinvolvement of ≥10% at baseline and an Eczema Area and Severity Indexscore of ≥16 at baseline.

An analysis was conducted for TRuE-AD1 and TRuE-AD2 patients having aBody Surface Area of atopic dermatitis involvement of ≥10% at baselineand an Eczema Area and Severity Index score of ≥16 at baseline. Of the81 patients in the subgroup, there were 13 patients receiving vehicle,36 patients receiving 0.75% BID ruxolitinib cream, and 32 patientsreceiving 1.5% BID cream. 100% of patients receiving vehicle and 1.5%BID ruxolitinib cream had an IGA score of 3 at baseline, while 33 of 36patients receiving 0.75% BID ruxolitinib cream had an IGA score of 3 atbaseline with the remaining patients having an IGA score of 2 atbaseline.

In both TRuE-AD1 and TRuE-AD2, for patients who have a Body Surface Areaof atopic dermatitis involvement of ≥10% at baseline and an Eczema Areaand Severity Index score of ≥16 at baseline, more patients treated withruxolitinib cream achieved IGA treatment success in the vehicle controlperiod at Week 2, Week 4, and Week 8 (0.75% BID, 30.6%, 38.9%, and50.0%; 1.5% BID, 25.0%, 46.9% and 59.4%) vs vehicle (0.0%) (FIG. 22 ).

In both TRuE-AD1 and TRuE-AD2, more patients treated with ruxolitinibcream achieved IGA treatment success in the vehicle control period atWeek 2, Week 4, and Week 8 (0.75% BID, 19.9%, 39.1%, and 44.7%; 1.5%BID, 26.2%, 45.1% and 52.6%) vs vehicle (3.7%, 6.1%, and 11.5%) (FIG. 27).

In TRuE-AD1 for patients who have an IGA score of 3 at baseline and aBody Surface Area of atopic dermatitis involvement of ≥10% at baseline,more patients treated with ruxolitinib cream achieved IGA treatmentsuccess in the vehicle control period at Week 2, Week 4, and Week 8(0.75% BID, 21.0%, 42.0%, and 53.0%; 1.5% BID, 25.3%, 50.6%, and 60.9%)vs vehicle (0.0%, 4.8%, and 14.3%).

In both TRuE-AD1 and TRuE-AD2, for patients who have a Body Surface Areaof atopic dermatitis involvement of ≥10% at baseline and an Eczema Areaand Severity Index score of ≥16 at baseline, EASI-75 was achieved bymore patients applying ruxolitinib cream 0.75% BID (36.1%, 63.9% and75.0% at Week 2, Week 4, and Week 8, respectively) and ruxolitinib cream1.5% BID (37.5%, 56.3%, and 71.9% at Week 2, Week 4, and Week 8,respectively) compared with vehicle (0%, 7.7%, and 7.7% at Week 2, Week4, and Week 8, respectively) (FIG. 23 ).

In both TRuE-AD1 and TRuE-AD2, EASI-75 was achieved by more patientsapplying ruxolitinib cream 0.75% BID (28.0%, 47.0% and 53.8% at Week 2,Week 4, and Week 8, respectively) and ruxolitinib cream 1.5% BID (33.9%,54.7%, and 62.0% at Week 2, Week 4, and Week 8, respectively) comparedwith vehicle (4.9%, 12.3%, and 19.7% at Week 2, Week 4, and Week 8,respectively) (FIG. 28 ).

In both TRuE-AD1 and TRuE-AD2, for patients who have a Body Surface Areaof atopic dermatitis involvement of ≥10% at baseline, an Eczema Area andSeverity Index score of ≥16 at baseline, and an itch Numerical RatingScale score of ≥4 at baseline, more patients achieved itch reductions(≥4-point improvement in itch NRS score) that applied ruxolitinib cream0.75% BID (23.1%, 42.3% and 50% at Week 2, Week 4, and Week 8,respectively) and ruxolitinib cream 1.5% BID (33.3%, 66.7%, and 61.1% atWeek 2, Week 4, and Week 8, respectively) on 1.5% BID compared withvehicle (0%, 27.3%, and 27.3% at Week 2, Week 4, and Week 8,respectively) (FIG. 24 ).

Surprisingly, these results show that patients with more severe atopicdermatitis with higher body surface involvement appear to respondcomparably or better on topical ruxolitinib cream 0.75% or 1.5% BID thanpatients treated with a systemic biologic agent like dupilumab (Seecomparison in Table 29; and FIG. 22-24 ). These results are particularlysurprising given that the responses for ruxolitinib cream were seen asearly as 4 to 8 weeks as compared to dupilumab at 16 weeks.

TABLE 29 Ruxolitinib cream Dupilumab^(b,c) At Week 4 At Week 8 At Week16 At Week 16 0.75% 1.5% 0.75% 1.5% 300 mg every 300 mg every Dosage BIDBID BID BID other week week Proportion of 38.9% 46.9% 50.0% 59.4% 36%,38% 36%, 37% patients achieving IGA-TS Proportion of 63.9% 75.0% 56.3%71.9% 44%, 51% 48%, 52% patients achieving EASI-75 Proportion of 42.3%  50% 66.7% 61.1% 36%, 41% 39%, 40% patient achieving a 4-pointimprovement in itch NRS score^(a) ^(a)Patients had an itch NRS score of≥4 at baseline. ^(b)Subcutaneous (Solo1 and Solo2 trials). ^(c)SimpsonEL, et al. “Two phase 3 trials of dupilumab versus placebo in atopicdermatitis,” N Engl J Med 2016; 375: 2335-48, Table 1.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentapplication is incorporated herein by reference in its entirety.

1.-30. (canceled)
 31. A method of treating mild to moderate atopicdermatitis in a human patient in need thereof comprising administeringto the human patient's skin a topical formulation, comprising 0.75%(w/w) on a free base basis of ruxolitinib, or a pharmaceuticallyacceptable salt thereof, two times per day.
 32. The method of claim 31,wherein the atopic dermatitis is moderate atopic dermatitis.
 33. Themethod of claim 31, wherein the human patient has a Body Surface Area(BSA) of atopic dermatitis involvement ranging from 3% to 20% atbaseline,
 34. The method of claim 31, wherein the patient has an itchNumerical Rating Scale score of ≥4 at baseline, and
 35. The method ofclaim 31, wherein further comprising continuing the administration ofthe topical formulation for at least about 8 weeks,
 36. The method ofclaim 31, wherein the human patient achieves at least a 4 pointreduction in itch Numerical Rating Scale score from baseline at week 8with administration.
 37. A method of treating moderate atopic dermatitisin a human patient in need thereof comprising: administering to thehuman patient's skin a topical formulation, comprising 0.75% (w/w) on afree base basis of ruxolitinib, or a pharmaceutically acceptable saltthereof, two times per day, and continuing the administration of thetopical formulation for at least about 8 weeks, wherein the humanpatient has a Body Surface Area (BSA) of atopic dermatitis involvementranging from 3% to 20% at baseline, wherein the patient has an itchNumerical Rating Scale score of ≥4 at baseline, and wherein the humanpatient achieves at least a 4 point reduction in itch Numerical RatingScale score from baseline at week 8 with administration.
 38. The methodof claim 37, wherein the human patient achieves IGA treatment success(IGA-TS) as a score of 0 (clear) or 1 (almost clear) with ≥2 gradeimprovement from baseline at week 8 of the administration.
 39. Themethod of claim 37, further comprising stopping the administration ofthe topical formulation after at least 8 weeks when the patient's skinresolves the atopic dermatitis.
 40. The method of claim 37, wherein thepatient achieves at least a 4 point reduction in itch Numerical RatingScale score from baseline at week 4 with administration.
 41. The methodof claim 37, wherein the patient achieves at least a 1 point reductionin itch Numerical Rating Scale score from baseline at day 1 of theadministration.
 42. The method of claim 37, wherein the patient achievesat least a 1 point reduction in itch Numerical Rating Scale score frombaseline at day 2 of said administration.
 43. The method of claim 37,wherein the human patient is aged 12 or older.
 44. The method of claim37, wherein the patient has been diagnosed with atopic dermatitis asdefined by the Hanifin and Rajka criteria.
 45. The method of claim 37,wherein the patient has a history of atopic dermatitis for at least 2years.
 46. The method of claim 37, wherein the ruxolitinib, or thepharmaceutically acceptable salt thereof, is ruxolitinib phosphate. 47.The method of claim 37, wherein the patient has a BSA of atopicdermatitis involvement of ≥10% at baseline.
 48. The method of claim 47,wherein the patient has an Eczema Area and Severity Index score of ≥16at baseline.
 49. The method of claim 37, wherein the ruxolitinib, or thepharmaceutically acceptable salt thereof, is ruxolitinib phosphate,wherein the human patient is aged 12 or older, and the patient has a BSAof atopic dermatitis involvement of ≥10% at baseline.
 50. The method ofclaim 49, wherein the patient has an Eczema Area and Severity Indexscore of ≥16 at baseline.
 51. The method of claim 38, wherein theruxolitinib, or the pharmaceutically acceptable salt thereof, isruxolitinib phosphate, wherein the human patient is aged 12 or older,and the patient has a BSA of atopic dermatitis involvement of ≥10% atbaseline.
 52. The method of claim 51, wherein the patient has an EczemaArea and Severity Index score of ≥16 at baseline.
 53. A method oftreating moderate atopic dermatitis in a human patient in need thereofcomprising: administering to the human patient's skin a topicalformulation, comprising 0.75% (w/w) on a free base basis of ruxolitinib,or a pharmaceutically acceptable salt thereof, two times per day, andcontinuing the administration of the topical formulation for at leastabout 8 weeks, wherein the human patient achieves at least a 4 pointreduction in itch Numerical Rating Scale score from baseline at week 8with administration, wherein the human patient achieves IGA treatmentsuccess (IGA-TS) as a score of 0 (clear) or 1 (almost clear) with ≥2grade improvement from baseline at week 8 of the administration, andwherein the patient: is aged 12 or older; has a history of AD for atleast 2 years; has an Investigator's Global Assessment score of 2 to 3at baseline; and has a Body Surface Area (BSA) of atopic dermatitisinvolvement ranging from 3% to 20% at baseline.
 54. The method of claim53, further comprising stopping the administration of the topicalformulation after at least 8 weeks when the patient's skin resolves theatopic dermatitis.
 55. The method of claim 53, wherein the patientachieves at least a 4 point reduction in itch Numerical Rating Scalescore from baseline at week 4 with administration.
 56. The method ofclaim 53, wherein the ruxolitinib, or the pharmaceutically acceptablesalt thereof, is ruxolitinib phosphate.